Search

BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system mediated by T cells. The Toll-like receptors (TLRs)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway plays an important role in the development of the disease. Exploring the specific mechanism of the signaling pathway is essential for further treatment of the disease and improving the prognosis of patients. OBJECTIVE: To review the TLRs/MyD88/NF-κB signaling pathway and its role in multiple sclerosis/experimental autoimmune encephalomyelitis models, which provides new ideas and strategies for the treatment of multiple sclerosis by inhibiting the TLRs/MyD88/NF-κB signaling pathway. METHODS: The literature related to the topic from January 2002 to December 2022 was searched in CNKI, WanFang and PubMed databases. A total of 61 articles were finally included for analysis. RESULTS AND CONCLUSION: The TLRs/MyD88/NF-κB signaling pathway is an important pathway that triggers a pro-inflammatory immune response. The TLRs/ MyD88/NF-κB signaling pathway plays an important role in the development of multiple sclerosis by regulating the antigen presentation of dendritic cells, destroying the integrity of the blood-brain barrier, and promoting the activation of T cells, B cells and microglia. By targeting TLRs, MyD88 and NF-κB molecules, inhibiting the activation or signal transduction of TLRs, MyD88 and NF-κB, and reducing the secretion of pro-inflammatory factors, multiple sclerosis can be treated. Animal studies have shown that active ingredients of traditional Chinese medicines, such as flavonoids and glycosides, and traditional Chinese medicine compound formulas, such as Buyang Huanwu Tang, can also treat experimental autoimmune encephalomyelitis by regulating the TLRs/MyD88/NF-κB signaling pathway, which points to the direction of searching for medicines targeting the TLRs/MyD88/NF-κB signaling pathway for the treatment of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Increased synthesis and deposition of collagen (COL) in the extracellular matrix (ECM) of equine endometrium contributes to endometrosis. Toll‐like receptors (TLRs) are transmembrane receptors involved in the innate immune response, recognized for their role in antigen recognition and previously associated with equine endometritis. The TLRs not only recognize pathogen‐associated molecular patterns but also regulate inflammations, fibrosis and cancer. The aim of this study was to explore the relationship between TLR expression at different stages of Kenney and Doig's (K‐D) grading and COL1 expression during the follicular phase of the oestrous cycle. Forty samples of endometrial tissues were collected post‐mortem from mares on the follicular phase of the oestrous cycle (10 samples of each K‐D category). Relative mRNA transcription of TLR‐2, TLR‐4 and COL1A2 genes was assessed using qPCR, and COL1 protein expression by Western blot analysis. The COL1A2 transcription increased in category IIB when compared to categories I, IIA and III endometria (p <.01). The relative protein abundance of COL1 showed no significant differences between endometrial categories (p >.05). As for the TLRs mRNA transcription, TLR‐2/‐4 transcripts increased in IIA when compared to the other K‐D endometria categories (p <.05). Our findings suggest that TLRs may be involved in the initiation of the endometrial inflammatory response. Additional studies are needed to explore TLRs' potential role as diagnostic markers for monitoring inflammation progression and fibrosis development, as well as their involvement in the mechanisms underlying fibrotic pathways. [ABSTRACT FROM AUTHOR]

Abstract Background Colon cancer remains a major health concern worldwide, with genetic factors playing a crucial role in its development. Toll-like receptors (TLRs) has been implicated in various cancers, but their role in colon cancer is not well understood. This study aims to identify functional polymorphisms in the promoter and 3′UTR regions of TLRs and evaluate their association with colon cancer susceptibility. Methods We conducted a case-control study involving 410 colon cancer patients and 410 healthy controls from the Chinese population. Genotyping of polymorphisms in TLR3, TLR4, TLR5 and TLR7 was performed using PCR-RFLP and TaqMan MGB probes. Using logistic regression analysis, we evaluated the association of TLRs polymorphisms and the susceptibility to colon cancer. To understand the biological implications of the TLR4 rs1927914 polymorphism, we conducted functional assays, including luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Results Our results demonstrated that the G-allele of the TLR4 rs1927914 polymorphism is significantly associated with a decreased risk of colon cancer (OR = 0.68, 95%CI = 0.50–0.91). Stratified analysis showed that TLR4 rs1927914 AG or GG genotype contributed to a decreased risk of colon cancer among younger individuals (OR = 0.52, 95%CI = 0.34–0.81), males (OR = 0.58, 95%CI = 0.38–0.87), non-smokers (OR = 0.58, 95%CI = 0.41–0.83) and non-drinker with OR (95%CI) of 0.66 (0.46–0.93). Functional assays demonstrated that in HCT116 and LOVO colon cancer cells, the luciferase activity driven by the TLR4 promoter with the rs1927914A allele was 5.43 and 2.07 times higher, respectively, compared to that driven by the promoter containing the rs1927914G allele. Electrophoretic mobility shift assay (EMSA) results indicated that the rs1927914G allele enhanced transcription factor binding. Using the transcription factor prediction tool, we found that the G allele facilitates binding of the repressive transcription factor Oct1, while the A allele does not. Conclusion The TLR4 rs1927914 polymorphism influence the susceptibility to colon cancer, with the G allele offering a protective effect through modulation of gene expression. These insights enhance our understanding of the genetic determinants of colon cancer risk and highlight TLR4 as a promising target for cancer prevention strategies.

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019–2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease. [ABSTRACT FROM AUTHOR]

As a highly organized system, endo‐lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo‐lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo‐lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll‐like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48‐linked polyubiquitination of LAMP‐1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP‐1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP‐1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most common kidney diseases, but its exact pathophysiology remains unknown. Toll-like receptors (TLRs) are innate immune receptors that recognize pathogen- and danger-associated molecular patterns, which can result in an inflammatory response. TLR4, TLR2, TLR5, TLR7, TLR8, TLR9, and TLR11 are essential in the pathogenesis of DN, according to recent evidence collected from both in vivo and in vitro studies. Studies have shown that TLR2 and TLR4 expression is higher in patients with renal failure and nephrotic diabetes. They also play critical roles in podocyte injury and inflammation caused by high glucose. TLR2 and TLR4 may be helpful therapeutic targets to prevent or delay DN in patients with type 2 diabetes mellitus. Additionally, TLR7 may contribute to kidney damage in type 1 diabetes mellitus, whereas downregulation of TLR9 expression inhibits inflammation and apoptosis pathways associated with DN. [ABSTRACT FROM AUTHOR]

As an important endogenous cytokine in mammals, interferon-γ (IFNγ) primes and significantly enhances the recognition and response of TLRs to pathogen-associated molecular patterns (PAMPs) in leukocytes. Subsequently, a series of phenomena in the TLR signalling pathway are activated, including increased expression of TLR mRNA, activation of the downstream signalling pathway mediated by myeloid differentiation primary response protein 88 (MyD88)-tumour necrosis factor receptor-associated factor 6 (TRAF6), and nuclear translocation of the nuclear transcription factor NF-κB. There is only one IFNγ isoform in mammals, while many fishes possess two IFNγ genes, IFNγ1 (also called IFNγ-rel) and IFNγ2. The aim of this work was to explore how these two IFNγ isoforms regulate the TLR signalling pathway in green-spotted pufferfish (Tetraodon nigroviridis). Real-time quantitative PCR (RT-qPCR) was performed to detect the expression of TLR1, TLR2, TLR3, TLR5, TLR7, TLR8, TLR9, MyD88, and TFAF6 in T. nigroviridis after stimulation with recombinant IFNγ1 (rIFNγ1) or rIFNγ2. Western blot analysis showed that the expression of MyD88, TFAF6, and NF-κB gradually increased between 0.5 and 8 h after stimulation with rTnIFNγ1. However, following treatment with IFNγ2, the expression of NF-κB at the protein level initially increased rapidly, only to decline swiftly thereafter. Meanwhile, the expression of MyD88 and TFAF6 exhibited a fluctuating pattern of rapid initial decline, subsequent rapid increase, and subsequent rapid decline. Electrophoretic mobility shift assay (EMSA) analysis showed that there was a significant and rapid shift of NF-κB within 5 min soon after rIFNγ2 stimulation, while rIFNγ1 had no significant effect. In summary, we revealed that IFNγ1 and IFNγ2 modulate the innate immune response via TLRs in T. nigroviridis and their regulatory mechanisms are different and multileveled. IFNγ1 and IFNγ2 could be used as immunomodulators to fine-tune the immune response of T. nigroviridis in different ways. [ABSTRACT FROM AUTHOR]

Mastitis is a significant inflammatory condition of the mammary gland in dairy cows. It is caused by bacterial infections and leads to substantial economic losses worldwide. The disease can be either clinical or sub-clinical and presents challenges such as reduced milk yield, increased treatment costs, and the need to cull affected cows. The pathogenic mechanisms of mastitis involve the activation of Toll-like receptors (TLRs), specifically TLR2 and TLR4. These receptors play crucial roles in recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses through the NF-κB signaling pathway. Recent in vitro studies have emphasized the importance of the TLR2/TLR4/NF-κB signaling pathway in the development of mastitis, suggesting its potential as a therapeutic target. This review summarizes recent research on the role of the TLR2/TLR4/NF-κB signaling pathway in mastitis. It focuses on how the activation of TLRs leads to the production of proinflammatory cytokines, which, in turn, exacerbate the inflammatory response by activating the NF-κB signaling pathway in mammary gland tissues. Additionally, the review discusses various bioactive compounds and probiotics that have been identified as potential therapeutic agents for preventing and treating mastitis by targeting TLR2/TLR4/NF-κB signaling pathway. Overall, this review highlights the significance of targeting the TLR2/TLR4/NF-κB signaling pathway to develop effective therapeutic strategies against mastitis, which can enhance dairy cow health and reduce economic losses in the dairy industry. [ABSTRACT FROM AUTHOR]

Nearly six million people worldwide have died from the coronavirus disease (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although COVID-19 vaccines are largely successful in reducing the severity of the disease and deaths, the decline in vaccine-induced immunity over time and the continuing emergence of new viral variants or mutations underscore the need for an alternative strategy for developing broad-spectrum host-mediated therapeutics against SARS-CoV-2. A key feature of severe COVID-19 is dysregulated innate immune signaling, culminating in a high expression of numerous pro-inflammatory cytokines and chemokines and a lack of antiviral interferons (IFNs), particularly type I (alpha and beta) and type III (lambda). As a natural host defense, the myeloid differentiation primary response protein, MyD88, plays pivotal roles in innate and acquired immune responses via the signal transduction pathways of Toll-like receptors (TLRs), a type of pathogen recognition receptors (PRRs). However, recent studies have highlighted that infection with viruses upregulates MyD88 expression and impairs the host antiviral response by negatively regulating type I IFN. Galectin-3 (Gal3), another key player in viral infections, has been shown to modulate the host immune response by regulating viral entry and activating TLRs, the NLRP3 inflammasome, and NF-κB, resulting in the release of pro-inflammatory cytokines and contributing to the overall inflammatory response, the so-called "cytokine storm". These studies suggest that the specific inhibition of MyD88 and Gal3 could be a promising therapy for COVID-19. This review presents future directions for MyD88- and Gal3-targeted antiviral drug discovery, highlighting the potential to restore host immunity in SARS-CoV-2 infections. [ABSTRACT FROM AUTHOR]

Background: The role of neutrophils in hepatitis B virus (HBV) infection has been a subject of debate due to their involvement in antiviral responses and immune regulation. This study aimed to elucidate the neutrophil characteristics in patients with chronic hepatitis B (CHB). Methods: Through flow cytometry and ribonucleic acid-sequencing analysis, the phenotypes and counts of neutrophils were analyzed in patients with CHB. Moreover, the effects of HBeAg on neutrophils and the corresponding pattern recognition receptors were identified. Simultaneously, the cross-talk between neutrophils and natural killer (NK) cells was investigated. Results: Neutrophils were activated in patients with CHB, characterized by higher expression levels of programmed death-ligand 1 (PD-L1), cluster of differentiation 86, and interleukin-8, and lower levels of CXC motif chemokine receptor (CXCR) 1 and CXCR2. Hepatitis B e antigen (HBeAg) partially induces neutrophil activation through the Toll-like receptor 2 (TLR2). A consistent upregulation of the TLR2 and HBeAg expression was observed in patients with CHB. Notably, the genes encoding molecules pivotal for NK-cell function upon NK receptor engagement enriched in neutrophils after HBeAg activation. The HBeAg-activated neutrophils demonstrated the ability to decrease the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in NK cells, while the PD-1 and PD-L1 pathways partially mediated the immunosuppression. Conclusions: The immunosuppression of neutrophils induced by HBeAg suggests a novel pathogenic mechanism contributing to immune tolerance in patients with CHB. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that inflammatory and immunologic processes play a significant role in the development and progression of glomerular diseases. Podocytes, the terminally differentiated epithelial cells, are crucial for maintaining the integrity of the glomerular filtration barrier. Once injured, podocytes cannot regenerate, leading to progressive proteinuric glomerular diseases. However, emerging evidence suggests that podocytes not only maintain the glomerular filtration barrier and are important targets of immune responses but also exhibit many features of immune-like cells, where they are involved in the modulation of the activity of innate and adaptive immunity. This dual role of podocytes may lead to the discovery and development of new therapeutic targets for treating glomerular diseases. This review aims to provide an overview of the innate immunity mechanisms involved in podocyte injury and the progression of proteinuric glomerular diseases. [ABSTRACT FROM AUTHOR]

Background: Toll‐like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole‐body immune and metabolic homeostasis. Objective: This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis‐induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC). Results: Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host‐microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases. Conclusion: Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat stress (HS) is currently one of the critical problems facing the global farmed broiler farming industry. After chronic HS, broiler production performance decreases, the body's antioxidant capacity decreases, oxidative stress occurs, and damage occurs in the splenic tissues, which causes an inflammatory response in the spleen through the inflammatory pathway, leading to a decline in immune function, which seriously affects the health of broilers. This is important for exploring the drugs that inhibit inflammatory responses to mitigate the harm HS triggers. This is important for exploring drugs to inhibit the inflammatory response to alleviate the damage caused by HS and to reduce the loss caused by HS in broiler breeding. The spleen is the largest peripheral immune organ of the organism, accounting for 25% of the total lymphoid tissue of the body. During HS, the spleen is damaged due to the elevated environment, which seriously affects life performance and broilers' health. This study aimed to investigate the mechanism of chronic HS damage to broiler spleen tissues. The broilers were typically raised until they reached 21 days of age, after which they were arbitrarily allocated into two groups: an HS group and a cntrol group. The HS group was subjected to a temperature of 35 °C for 10 h each day, starting at 21 days of age. At 35 and 42 days of age, spleen and serum samples were obtained from the broilers. The results showed that after HS, a significant decrease in productive performance was observed at 42 days of age (p < 0.01), and the spleen index, and bursa index were significantly decreased (p < 0.01). T-AOC of the organism was significantly decreased (p < 0.05), GSH-PX, SOD, and CAT antioxidant factors were significantly decreased (p < 0.01), and MDA was significantly elevated (p < 0.01). HS also led to a significant increase in cytokines IL-6, TNF-α, and INF-γ and a significant decrease in IL-4 in the spleen. The histopathologic results showed that the spleen's red-white medulla was poorly demarcated. The cells were sparsely arranged after HS. After HS, the expression of TLRs, MYD88, and NF-κB genes increased significantly. The expression of HSP70 increased significantly, suggesting that HS may induces an inflammatory response in broiler spleens through this signaling pathway, which may cause pathological damage to broiler spleens, leading to a decrease in immune function and progressively aggravating HS-induced damage with the prolongation of HS. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of Chlamydia trachomatis is associated with the induction of the host inflammatory response; however, the precise underlying molecular mechanisms remain poorly understood. Methods CT622, a T3SS effector protein, has an important role in the pathogenesis of C trachomatis ; however, whether CT622 can induce a host inflammatory response is not understood. Our findings demonstrate that CT622 induces the expression of interleukins 6 and 8 (IL-6 and IL-8). Mechanistically, these effects involve the activation of the MAPK/NF-κB signaling pathways (mitogen-activated protein kinase/nuclear factor κB). Results Interestingly, we demonstrated that the suppression of toll-like receptor 4 using small interfering RNA markedly reduced the phosphorylation of ERK, p38, JNK, and IκBα, concomitant with a significant decrease in IL-6 and IL-8 secretion. Conversely, disruption of toll-like receptor 2 abrogated the CT622-induced upregulation of IL-8 and activation of ERK, whereas IL-6 expression and p38, JNK, and IκBα phosphorylation were unaffected. Conclusions Taken together, these results indicate that CT622 contributes to the inflammatory response through the toll-like receptor 2/4–mediated MAPK/NF-κB pathways, which provides insight into the molecular pathology of C trachomatis infection. [ABSTRACT FROM AUTHOR]

Background: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s). Methods: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-κB phosphorylation, and they have been silenced with specific small interfering RNAs. Results: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals. Conclusions: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects. [ABSTRACT FROM AUTHOR]

Bacillus Calmette-Gué rin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumorally BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma. [ABSTRACT FROM AUTHOR]

Global fire activities, which are getting worse due to climate change, cause both environmental and human health hazards. Firefighters, being the first responders, are frequently exposed to heat which may impact their immune system and overall health. However, the nature of the impact of chronic heat exposure on immune function has not been studied in-depth in firefighters. In this study, 22 firefighters exposed to "heavy-smoke fires (structural fires)", categorized as the "high-exposure group" (>0.15 structural fires/week) and "low-exposure group" (<0.15 structural fires/week), were sampled. Peripheral blood was examined for immune cell profile based on total and differential cell counts, immune function based on the transcriptional expression of drivers of innate and adaptive immunity and key inflammation mediators, and heat stress marker HSP70. The white blood cell (WBC) count, mean corpuscular volume, mean corpuscular hemoglobin, and absolute and segmented neutrophil counts decreased below the normal range in both exposure groups. The gene transcript levels for toll-like receptors (TLR2, TLR4, but not TLR7) and their adaptor protein MYD88 were lower whereas those for T-cell transcription factors (RORC/RORγ, FoxP3) and inflammatory mediators (TNF-α, Granzyme-B) were higher in the "high-exposure group", indicating mixed response; however, the ratios between pro-inflammatory and anti-inflammatory transcription factors of adaptive immunity, namely T-bet/FoxP3 (Th1/Treg) and RORC/FoxP3 (Th17/Treg), were lower. Collectively, decreased immune cell landscape, downregulated key innate immunity receptors, and Tregs' dominance suggested that chronic heat exposure in firefighters dysregulated innate and adaptive immunity, skewed towards an overall immunosuppressive condition with inflammation. [ABSTRACT FROM AUTHOR]

Abstract As a highly organized system, endo‐lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo‐lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo‐lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll‐like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48‐linked polyubiquitination of LAMP‐1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP‐1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP‐1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs.

Abstract Background Toll‐like receptors (TLRs) are a family of fundamental pattern recognition receptors in the innate immune system, constituting the first line of defense against endogenous and exogenous antigens. The gut microbiota, a collection of commensal microorganisms in the intestine, is a major source of exogenous antigens. The components and metabolites of the gut microbiota interact with specific TLRs to contribute to whole‐body immune and metabolic homeostasis. Objective This review aims to summarize the interaction between the gut microbiota and TLR signaling pathways and to enumerate the role of microbiota dysbiosis‐induced TLR signaling pathways in obesity, inflammatory bowel disease (IBD), and colorectal cancer (CRC). Results Through the recognition of TLRs, the microbiota facilitates the development of both the innate and adaptive immune systems, while the immune system monitors dynamic changes in the commensal bacteria to maintain the balance of the host‐microorganism symbiosis. Dysbiosis of the gut microbiota can induce a cascade of inflammatory and metabolic responses mediated by TLR signaling pathways, potentially resulting in various metabolic and inflammatory diseases. Conclusion Understanding the crosstalk between TLRs and the gut microbiota contributes to potential therapeutic applications in related diseases, offering new avenues for treatment strategies in conditions like obesity, IBD, and CRC.

Probiotics have been reported to have immunomodulatory properties in the context of infectious disease and inflammation, although the underlying mechanisms are not fully understood. Here, we aimed to determine how different probiotic bacterial strains modulated macrophage function during TLR3 stimulation mimicking viral infection. We screened 14 different strains for their ability to modulate TNF‐α, IL‐6 IL‐10, IFN‐α, IFN‐β and IFN‐γ secretion in RAW 264.7 macrophages with or without poly(I:C) stimulation. Seven strains were selected for further analysis using primary porcine alveolar macrophages. In‐depth transcriptomic analysis on alveolar macrophages was conducted for two strains. Most strains induced a synergistic effect when co‐incubated with poly(I:C) resulting in increased levels of IL‐6 and TNF‐α secretion from RAW 264.7 cells. This synergistic effect was found to be TLR2 independent. Only strains of Bacillus spp. could induce this effect in alveolar macrophages. Transcriptomic analysis indicated that the increased TNF‐α secretion in alveolar macrophages after co‐incubation with poly(I:C) correlated with significant upregulation of TNF and IL23A‐related pathways. Collectively, our data show that probiotic bacteria possess strain‐dependent immunomodulatory properties that may be harnessed to enhance innate immune responses to pathogens. [ABSTRACT FROM AUTHOR]

The new and evolving paradigms of psychiatric disorders pathogenesis are deeply inclined toward chronic inflammation that leads to disturbances in the neuronal networks of patients. A strong association has been established between the inflammation and neurobiology of depression which is mediated by different toll-like receptors (TLRs). TLRs and associated signalling pathways are identified as key immune regulators to stress and infections in neurobiology. They are a special class of transmembrane proteins, which are one of the broadly studied members of the Pattern Recognition Patterns family. This review focuses on summarizing the important findings on the role of TLRs associated with psychotic disorders and acquired epilepsy. This review also shows the promising potential of TLRs in immune response mediated through antidepressant therapies and TLRs polymorphism associated with various psychotic disorders. Moreover, this also sheds light on future directions to further target TLRs as a therapeutic approach for psychiatric disorders. [ABSTRACT FROM AUTHOR]

BackgroundIn early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s).MethodsSP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs.ResultsSPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56brightNK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56dimNK cell functions in COVID-19 recovered, but not in non-infected, individuals.ConclusionsTLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID‐19 subjects.

Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.

Mastitis is a significant inflammatory condition of the mammary gland in dairy cows. It is caused by bacterial infections and leads to substantial economic losses worldwide. The disease can be either clinical or sub-clinical and presents challenges such as reduced milk yield, increased treatment costs, and the need to cull affected cows. The pathogenic mechanisms of mastitis involve the activation of Toll-like receptors (TLRs), specifically TLR2 and TLR4. These receptors play crucial roles in recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses through the NF-κB signaling pathway. Recent in vitro studies have emphasized the importance of the TLR2/TLR4/NF-κB signaling pathway in the development of mastitis, suggesting its potential as a therapeutic target. This review summarizes recent research on the role of the TLR2/TLR4/NF-κB signaling pathway in mastitis. It focuses on how the activation of TLRs leads to the production of proinflammatory cytokines, which, in turn, exacerbate the inflammatory response by activating the NF-κB signaling pathway in mammary gland tissues. Additionally, the review discusses various bioactive compounds and probiotics that have been identified as potential therapeutic agents for preventing and treating mastitis by targeting TLR2/TLR4/NF-κB signaling pathway. Overall, this review highlights the significance of targeting the TLR2/TLR4/NF-κB signaling pathway to develop effective therapeutic strategies against mastitis, which can enhance dairy cow health and reduce economic losses in the dairy industry.

The spleen is the largest peripheral immune organ of the organism, accounting for 25% of the total lymphoid tissue of the body. During HS, the spleen is damaged due to the elevated environment, which seriously affects life performance and broilers’ health. This study aimed to investigate the mechanism of chronic HS damage to broiler spleen tissues. The broilers were typically raised until they reached 21 days of age, after which they were arbitrarily allocated into two groups: an HS group and a cntrol group. The HS group was subjected to a temperature of 35 °C for 10 h each day, starting at 21 days of age. At 35 and 42 days of age, spleen and serum samples were obtained from the broilers. The results showed that after HS, a significant decrease in productive performance was observed at 42 days of age (p < 0.01), and the spleen index, and bursa index were significantly decreased (p < 0.01). T-AOC of the organism was significantly decreased (p < 0.05), GSH-PX, SOD, and CAT antioxidant factors were significantly decreased (p < 0.01), and MDA was significantly elevated (p < 0.01). HS also led to a significant increase in cytokines IL-6, TNF-α, and INF-γ and a significant decrease in IL-4 in the spleen. The histopathologic results showed that the spleen’s red-white medulla was poorly demarcated. The cells were sparsely arranged after HS. After HS, the expression of TLRs, MYD88, and NF-κB genes increased significantly. The expression of HSP70 increased significantly, suggesting that HS may induces an inflammatory response in broiler spleens through this signaling pathway, which may cause pathological damage to broiler spleens, leading to a decrease in immune function and progressively aggravating HS-induced damage with the prolongation of HS.

Accumulating evidence indicates that inflammatory and immunologic processes play a significant role in the development and progression of glomerular diseases. Podocytes, the terminally differentiated epithelial cells, are crucial for maintaining the integrity of the glomerular filtration barrier. Once injured, podocytes cannot regenerate, leading to progressive proteinuric glomerular diseases. However, emerging evidence suggests that podocytes not only maintain the glomerular filtration barrier and are important targets of immune responses but also exhibit many features of immune-like cells, where they are involved in the modulation of the activity of innate and adaptive immunity. This dual role of podocytes may lead to the discovery and development of new therapeutic targets for treating glomerular diseases. This review aims to provide an overview of the innate immunity mechanisms involved in podocyte injury and the progression of proteinuric glomerular diseases.

Cardiosphere-derived cells (CDCs) are currently being evaluated in clinical trials as a potential therapeutic tool for regenerative medicine. The effectiveness of transplanted CDCs is largely attributed to their ability to release beneficial soluble factors to enhance therapeutic effects. An emerging area of research is the pretreatment of stem cells, including CDCs, with various cytokines to improve their therapeutic properties. This strategy aims to enhance their survival, proliferation, differentiation, and paracrine activities after transplantation. In our study, we investigated the differential effects of various cytokines and TLR ligands on the secretory phenotype of human CDCs. Using a magnetic bead-based immunoassay, we analyzed the CDCs-conditioned media for 41 cytokines and growth factors and detected the presence of 21 cytokines. We found that CDC incubation with lipopolysaccharide, a TLR4 ligand, and the cytokine combination of TNF/IFN significantly increased the secretion of most of the cytokines detected. Specifically, we observed an increased secretion and gene expression of IP10, MCP3, IL8, and VEGFA. In contrast, the TLR3 ligand polyinosinic-polycytidylic acid and TGF-beta had minimal effects on CDC cytokine secretion. Additionally, TNF/IFN, but not LPS, enhanced ICAM1 expression. Our findings offer new insights into the role of cytokines in potentially modulating the biology and regenerative potential of CDCs. [ABSTRACT FROM AUTHOR]

The present study was conducted on three hundred commercial broiler chicks with the aim to evaluate the effect of black pepper supplementation on expression of TLR gene where the negative control (T1) group was given basal diet without antibiotic and in the control group (T2) basal diet with antibiotic was fed, third (T3), fourth (T4), fifth (T5) and sixth (T6) groups were supplemented with black pepper powder (BPP) at levels 0.25, 0.5, 0.75 and 1%, respectively in diet. After 42 days, a significant reduction (p < 0.05) in ileal E. coli count and a higher value of Lactobacilli was recorded in the various black pepper powder supplemented groups, and they differed significantly (p < 0.05) from negative control. The mRNA expression levels of Toll-like receptors (TLR 2 and TLR 4) had shown significant (p < 0.05) changes in experimental groups. The TLR 2 and TLR 4 genes revealed differential expression in all black pepper supplemented groups in comparison to negative control and control group, while TLR 7 did not show any significant change. Thus, supplementation of black pepper powder can be exploited as an immunomodulator to enhance adaptive immune response of broiler chicks after validation on large number of samples. [ABSTRACT FROM AUTHOR]

Enteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen associated with persistent diarrhea in travelers, immunocompromised patients and children worldwide. However, the pathogenesis of this organism is yet to be established. In this study, the role of Toll-like receptors (TLRs) was evaluated in epidermal growth factor receptor (EGFR)-mediated IL-8 secretion by EAEC-infected human small intestinal and colonic epithelial cells (INT-407 and HCT-15, respectively). We observed that EAEC-induced upregulation of TLR2, TLR4 and TLR5 transcripts in both types of cells, and the maximum level of these transcripts was seen in cells infected with EAEC-T8 (an invasive clinical isolate). All these TLRs made a significant contribution to the EAEC-T8-mediated EGFR activation in these cells. Furthermore, these TLRs were found to be associated with activation of the downstream effectors (ERK-1/2, PI3 kinase and Akt) and transcription factors (NF-κB, c-Jun, c-Fos and STAT-3) of EGFR-mediated signal transduction pathways. Moreover, the involvement of these TLRs was also noted in IL-8 secretion by both EAEC-T8-infected cell types. Our findings suggest that EAEC-induced upregulation of TLR2, TLR4 and TLR5 is important for the IL-8 response via EGFR-mediated signal transduction pathways in these cells. [ABSTRACT FROM AUTHOR]

HIV infection impairs host immunity, leading to progressive disease. An anti-retroviral treatment efficiently controls viremia but cannot completely restore the immune dysfunction in HIV-infected individuals. Both host and viral factors determine the rate of disease progression. Among the host factors, innate immunity plays a critical role; however, the mechanism(s) associated with dysfunctional innate responses are poorly understood among HIV disease progressors, which was investigated here. The gene expression profiles of TLRs and innate cytokines in HIV-infected (LTNPs and progressors) and HIV-uninfected individuals were examined. Since the progressors showed a dysregulated TLR-mediated innate response, we investigated the role of TLR agonists in restoring the innate functions of the progressors. The stimulation of PBMCs with TLR3 agonist-poly:(I:C), TLR7 agonist-GS-9620 and TLR9 agonist-ODN 2216 resulted in an increased expression of IFN-α, IFN-β and IL-6. Interestingly, the expression of IFITM3, BST-2, IFITM-3, IFI-16 was also increased upon stimulation with TLR3 and TLR7 agonists, respectively. To further understand the molecular mechanism involved, the role of miR-155 was explored. Increased miR-155 expression was noted among the progressors. MiR-155 inhibition upregulated the expression of TLR3, NF-κB, IRF-3, TNF-α and the APOBEC-3G, IFITM-3, IFI-16 and BST-2 genes in the PBMCs of the progressors. To conclude, miR-155 negatively regulates TLR-mediated cytokines as wel l as the expression of host restriction factors, which play an important role in mounting anti-HIV responses; hence, targeting miR-155 might be helpful in devising strategic approaches towards alleviating HIV disease progression. [ABSTRACT FROM AUTHOR]

Toll‐Like Receptors (TLRs) play a pivotal role in immunity by recognising conserved structural features of pathogens and initiating the innate immune response. TLR signalling is subject to complex regulation that remains poorly understood. Here we show that two small type I transmembrane receptors, TMED2 and 7, that function as cargo sorting adaptors in the early secretory pathway are required for transport of TLRs from the ER to Golgi. Protein interaction studies reveal that TMED7 interacts with TLR2, TLR4 and TLR5 but not with TLR3 and TLR9. On the other hand, TMED2 interacts with TLR2, TLR4 and TLR3. Dominant negative forms of TMED7 suppress the export of cell surface TLRs from the ER to the Golgi. By contrast TMED2 is required for the ER‐export of both plasma membrane and endosomal TLRs. Together, these findings suggest that association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi. [ABSTRACT FROM AUTHOR]

The innate immune system is critical for inducing durable and protective T cell responses to infection and has been increasingly recognized as a target for cancer immunotherapy. In this review, we present a framework wherein distinct innate immune signaling pathways activate five key dendritic cell activities that are important for T cell-mediated immunity. We discuss molecular pathways that can agonize these activities and highlight that no single pathway can agonize all activities needed for durable immunity. The immunological distinctions between innate immunotherapy administration to the tumor microenvironment versus administration via vaccination are examined, with particular focus on the strategies that enhance dendritic cell migration, interferon expression, and interleukin-1 family cytokine production. In this context, we argue for the importance of appreciating necessity vs. sufficiency when considering the impact of innate immune signaling in inflammation and protective immunity and offer a conceptual guideline for the development of efficacious cancer immunotherapies. Innate immune pathways are commonly discussed targets of cancer immunotherapy. Cao and Kagan review the state of this rapidly advancing field of study. They introduce the concept that five key innate immune activities in dendritic cells are needed to stimulate durable T cell-mediated anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Background: The African swine fever (ASF) virus (ASFV) and ASF-like viral sequences were identified in human samples and sewage as well as in different water environments. Pigs regularly experience infections by the ASFV. The considerable stability of the virus in the environment suggests that there is ongoing and long-term contact between humans and the ASFV. However, humans exhibit resistance to the ASFV, and the decisive factor in developing infection in the body is most likely the reaction of target macrophages to the virus. Therefore, this study aimed to characterize the responses of human macrophages to the virus and explore the distinct features of the viral replication cycle within human macrophages. Methods: The ASFV Armenia/07 strain was used in all experiments. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the ASFV gene expression; flow cytometry analysis was performed to evaluate the effects of the inactive and active ASFV (inASFV and aASFV) treatments on the phenotype of THP-1-derived macrophages (Mφ0) and inflammatory markers. Moreover, other methods such as cell viability and apoptosis assays, staining techniques, phagocytosis assay, lysosome-associated membrane protein (LAMP-1) cytometry, and cytokine detection were used during experiments. Results: Our findings showed that the virus initiated replication by entering human macrophages. Subsequently, the virus shed its capsid and initiated the transcription of numerous viral genes, and at least some of these genes executed their functions. In THP-1-derived macrophages (Mφ0), the ASFV implemented several functions to suppress cell activity, although the timing of their implementation was slower compared with virus-sensitive porcine alveolar macrophages (PAMs). Additionally, the virus could not complete the entire replication cycle in human Mφ0, as indicated by the absence of viral factories and a decrease in infectious titers of the virus with each subsequent passage. Overall, the infection of Mφ0 with the ASFV caused significant alterations in their phenotype and functions, such as increased TLR2, TLR3, CD80, CD36, CD163, CXCR2, and surface LAMP-1 expression. Increased production of the tumor necrosis factor (TNF) and interleukin (IL)-10 and decreased production of interferon (IFN)-α were also observed. Taken together, the virus enters human THP-1-derived macrophages, starts transcription, and causes immunological responses by target cells but cannot complete the replicative cycle. Conclusion: These findings suggest that there may be molecular limitations within human macrophages that at least partially restrict the complete replication of the ASFV. Understanding the factors that hinder viral replication in Mφ0 can provide valuable insights into the host–virus interactions and the mechanisms underlying the resistance of human macrophages to the ASFV.

Background: Disease risk variants are likely to affect gene expression in a context- and cell-type specific manner. The membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs8736 metabolic-dysfunction-associated fatty liver disease (MAFLD)-risk variant was recently reported to be a negative regulator of toll-like receptors (TLRs) signalling in macrophages. Whether this effect is generic or cell-type specific in immune cells is unknown. Methods: We investigated the impact of modulating TLR signaling on MBOAT7 expression in peripheral blood mononuclear cells (PBMCs). We also examined whether the rs8736 polymorphism in MBOAT7 regulates this effect. Furthermore, we measured the allele-specific expression of MBOAT7 in various immune cell populations under both unstimulated and stimulated conditions. Results: We show that MBOAT7 is down-regulated by TLRs in PBMCs. This effect is modulated by the MBOAT7 rs8736 polymorphism. Additionally, we provide evidence that MBOAT7 acts primarily as a modulator of TLR signalling in mononuclear phagocytes. Conclusion: Our results highlight the importance of studying Genome-Wide Association Studies (GWAS) signals in the specific cell types in which alterations of gene expression are found.

The Patagonian moray cod, Muraenolepis orangiensis, belongs to the family Muraenolepididae and is the sole order of Gadiformes that inhabits the temperate and cold waters of the southern hemisphere. One of the features of the Gadiformes order is that they have a remarkably unique immune gene repertoire that influences innate and adaptive immunity, and they lack major histocompatibility complex (MHC) class II, invariant chains (CD74), and CD4 genes. In this study, a high-quality chromosome-level genome assembly was constructed, resulting in a final assembled genome of 893.75 Mb, with an N50 scaffold length of 30.07 Mb and the longest scaffold being 39.77 Mb. Twenty-five high-quality pseudochromosomes were assembled, and the complete BUSCO rate was 93.4%. A total of 34,553 genes were structurally annotated, and 27,691 genes were functionally annotated. Among the 10 primary genes involved in MHC class II, only two ERAP1 genes and one AIRE gene were identified through the genome study. Although no specific reason for the MHC class II deficiency has been identified, it has been shown that the toll-like receptors (TLRs), which are significant to the innate immune response, are significantly expanded in M. orangiensis. A total of 44 TLRs have been identified, with 32 TLR13 genes distributed evenly on six different pseudochromosomes. This study is the first to reveal the whole genome of a Muraenolepididae family and provides valuable insights into the potential rationale for the MHC class II deficiency in a Gadiformes fish species.

Red blood cells (RBCs) are the most abundant cell types in the circulatory system of vertebrates. In fish, RBCs retain their nuclei throughout their lifetime and remain transcriptionally and translationally active. While their primary function is typically associated with gas exchange, recent reports indicate that nucleated red blood cells can play a significant role in regulating the body's innate immune response. The current article describes the innate immune role of red blood cells in rohu (Labeo rohita), a freshwater fish species that holds significant commercial importance in India and South‐East Asian nations. From the whole blood and mucosal surface RBCs have been isolated through density gradient centrifugation with HiSep™LSM 1077 (density 1.007 ± 0.0010) and their purity has been confirmed by the Giemsa staining followed by microscopical observations. Toll‐like receptors (TLR2, 3, 4, 5) and nucleotide oligomerization domain (NOD)‐like receptors (NOD1 and NOD2) in RBCs of rohu fingerlings were observed to be significantly activated (P < 0.05) on infection with Aeromonas hydrophila and Edwardsiella tarda. This activation resulted in increased expression of interleukins (IL‐8, IL‐1β) and interferon (IFN)‐I genes. The activation of TLR4, NOD1 and NOD2, as well as the expression of interleukins and IFN‐I genes have been observed in both in vivo and in vitro stimulation of rohu RBCs with lipopolysaccharides. These findings highlight the importance of fish RBCs in enhancing innate immunity against various pathogenic invasions in rohu. [ABSTRACT FROM AUTHOR]

To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage's sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1(+) and Spike-1(−) lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3(+) alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163(+) myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19. [ABSTRACT FROM AUTHOR]

Endosomal toll‐like receptors (TLRs) must be translocated from the endoplasmic reticulum (ER) to the endosome and proteolytically cleaved within the endosome before they can induce cellular signals. As ligands for these TLRs are also liberated from apoptotic or necrotic cells, this process is controlled by several mechanisms which shall ensure that there is no inadvertent activation. We have shown previously that antiphospholipid antibodies induce endosomal NADPH‐oxidase (NOX) followed by the translocation of TLR7/8 to the endosome. We show now that endosomal NOX is required for the rapid translocation of TLR3, TLR7/8, and TLR9. Deficiency of gp91phox, the catalytic subunit of NOX2, or inhibition of endosomal NOX by the chloride channel blocker niflumic acid both prevent immediate (i.e., within 30 min) translocation of these TLRs as shown by confocal laser scanning microscopy. Under these conditions, the induction of mRNA synthesis for TNF‐α and secretion of TNF‐α is delayed by approx. 6–9 h. However, maximal expression of TNF‐α mRNA or secretion of TNF‐α is not significantly reduced. In conclusion, these data add NOX2 as another component involved in the orchestration of cellular responses to ligands of endosomal TLRs. [ABSTRACT FROM AUTHOR]

Introduction: Despite intensive research, preterm birth (PTB) rates have not decreased significantly in recent years due to a lack of understanding of the underlying causes and insufficient treatment options for PTB. We are committed to finding promising biomarkers for the treatment of PTB. Methods: An extensive search of the literature was conducted with MEDLINE/PubMed, and in total, 151 studies were included and summarized in the present review. Results: Substantial evidence supports that the infection and/or inflammatory cascade associated with infection is an early event in PTB. Toll-like receptor (TLR) is a prominent pattern recognition receptor (PRR) found on both immune and non-immune cells, including fetal membrane cells. The activation of TLR downstream molecules, followed by TLR binding to its ligand, is critical for infection and inflammation, leading to the involvement of the TLR signaling pathway in PTB. TLR ligands are derived from microbial components and molecules released by damaged and dead cells. Particularly, TLR4 is an essential TLR because of its ability to recognize lipopolysaccharide (LPS). In this comprehensive overview, we discuss the role of TLR signaling in PTB, focus on numerous host-derived genetic and epigenetic regulators of the TLR signaling pathway, and cover ongoing research and prospective therapeutic options for treating PTB by inhibiting TLR signaling. Conclusion: This is a critical topic because TLR-related molecules and mechanisms may enable obstetricians to better understand the physiological changes in PTB and develop new treatment and prevention strategies. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are essential receptors of the innate immune system, playing a significant role in cardiovascular diseases. TLR4, with the highest expression among TLRs in the heart, has been investigated extensively for its critical role in different myocardial inflammatory conditions. Studies suggest that inhibition of TLR4 signaling pathways reduces inflammatory responses and even prevents additional injuries to the already damaged myocardium. Recent research results have led to a hypothesis that there may be a relation between TLR4 expression and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in various inflammatory conditions, including cardiovascular diseases. AMPK, as a cellular energy sensor, has been reported to show anti-inflammatory effects in various models of inflammatory diseases. AMPK, in addition to its physiological acts in the heart, plays an essential role in myocardial ischemia and hypoxia by activating various energy production pathways. Herein we will discuss the role of TLR4 and AMPK in cardiovascular diseases and a possible relation between TLRs and AMPK as a novel therapeutic target. In our opinion, AMPK-related TLR modulators will find application in treating different immune-mediated inflammatory disorders, especially inflammatory cardiac diseases, and present an option that will be widely used in clinical practice in the future.

Abstract Japanese encephalitis (JE) disease, a viral brain fever is caused by Japanese encephalitis virus (JEV). Despite the availability of effective vaccines against this deadly infection, JE is the leading cause of epidemic viral encephalitis in children in South-east Asia. There is no treatment available for the JE disease which might be due to incomplete understanding of the pathogenesis of JE virus. The JEV infections lead to permanent neurological deficits even in those who survive from the infection. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Microglial activation, proinflammatory cytokine release and leukocytes trafficking are associated following JEV infection in central nervous system (CNS). How the pattern recognition receptors sense the viral nucleic acid and how the microglial and neuronal cells behaves following JEV infection is still unelucidated. There is scarcity of data on the expression levels of toll like receptors (TLRs), cytokines and chemokines in JEV infection in invitro model. To explore the molecular mechanisms of JEV infection of microglial cells and neuronal cells, we studied the expression profile of TLRs, cytokines and chemokines in JEV infected microglial cell line BV2 and Neuronal cell line Neuro 2A. For the present study, we developed the mouse model of encephalitis by intracerebral (IC) injection of JE virus for virus propagation, disease progression and damage study. Our results demonstrate the exaggerated release of some specific TLRs, cytokines and chemokines in invitro cell culture of microglial and Neuro 2A cell line, which are associated with bad outcome in invivo study.

Purpose of the study. To evaluate the number of cells with the CD45+/- phenotype expressing Toll-like receptors (TLRs) in tissues of the tumor, peritumoral area and resection line tissues in colon cancer (CC) with various tumor locations.Materials and methods. The study included 50 patients with CC. All patients underwent surgery as the primary treatment, and tissue material was collected from the patients. Expression of TLRs (2, 3, 4, 8, 9) on CD45+, CD45- cell populations was determined by flow cytometry in cell suspensions obtained from tissues of the tumor, peritumoral area (1–3 cm from the tumor) and resection line tissues (~10 cm from the tumor) with further calculation of the percentage of cells with the corresponding phenotype from the total number of cells.Results. An analysis of left-sided colon tumors showed lower percentage of CD45- cells expressing TLR4, 8, compared to rightsided tumors, by 38 % and 25 %. A comparative analysis of the number of CD45+ cells expressing TLR 2, 4 showed their decrease by 81 % and 87 %, respectively, compared with right-sided tumors. An assessment of the data in the perifocal zone of left-sided colon tumors, compared with right-sided ones, demonstrated a decrease in the percentage of cells with the CD45- phenotype that express TLR4, by 61 %. Resection line tissues in left-sided tumors, compared with right-sided ones, showed a statistically significant increase in the percentage of CD45- cells that express TLR 2, 4 by 205 % and 55 %, respectively. The number of CD45+ cells expressing TLR 4 decreased by 87 %. An assessment of the number of cells expressing TLRs 3 and 9 in the tumor, peritumoral area and resection line tissues did not reveal significant differences.Conclusions. Lower number of cells with CD45+ and CD45- phenotypes express TLRs 2, 4, 8 in left-sided colon tumors and their peritumoral tissues, compared to right-sided cancer.

This pilot study used an alternative and economically efficient technique, the Kompetitive Allele-Specific Polymerase Chain Reaction (KASP-PCR) to examine 48 SNPs from 11 parasite-resistance genes found on 8 chromosomes in 110 animals from five sheep breeds reared in Hungary; Hungarian Tsigai, White Dorper, Dorper, Ile de France, and Hungarian Merino. Allele and genotype frequencies, fixation index, observed heterozygosity, expected heterozygosity, F statistic, and their relationship with the Hardy–Weinberg equilibrium (WHE) and the polymorphic information content (PIC) were determined, followed by principal component analysis (PCA). As much as 32 SNPs out of the 48 initially studied were successfully genotyped. A total of 9 SNPs, 4 SNPs in TLR5, 1 SNP in TLR8, and 4 SNPs in TLR2 genes, were polymorphic. The variable genotype and allele frequency of the TLRs gene indicated genetic variability among the studied sheep breeds, with the Hungarian Merino exhibiting the most polymorphisms, while Dorper was the population with the most SNPs departing from the HWE. According to the PIC value, the rs430457884-TLR2, rs55631273-TLR2, and rs416833129-TLR5 were found to be informative in detecting polymorphisms among individuals within the populations, whereas the rs429546187-TLR5 and rs424975389-TLR5 were found to have a significant influence in clustering the population studied. This study reported a moderate level of genetic variability and that a low to moderate within-breed diversity was maintained in the studied populations. [ABSTRACT FROM AUTHOR]

Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-kB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1b, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4+ T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-kB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases. [ABSTRACT FROM AUTHOR]

Evolocumab, a PCSK-9 inhibitor, is known for its ability to reduce low-density lipoprotein cholesterol (LDL-C). This study aimed to investigate the effects of evolocumab, alone or in combination with atorvastatin, on the progression of atherosclerosis. Fifty male domestic rabbits were randomly assigned to five groups: control, high cholesterol diet, evolocumab vehicle (dimethyl sulfoxide, DMSO), evolocumab alone, and evolocumab plus atorvastatin. Serum levels of interleukin 10 (IL-10), IL-17, IL-1ß, intracellular adhesion molecule (ICAM), and vascular adhesion molecule (VCAM) were measured. Toll-like receptor (TLR) expression on monocytes was evaluated using flow cytometry. Histopathological examination and measurement of intimal thickness (IT) were also conducted. The results revealed that the evolocumab produced a statistically significant (p<0.05) reduction in lipid profile at 5 weeks, with the peak effect occurring at 10 weeks. Furthermore, the inhibitor reduced TLRs at 10 weeks to 10.83±1.8 and intimal thickness to 160.66±9.45. IL-17, IL-1ß, ICAM, and VCAM were significantly reduced by evolocumab treatment, with the improvement of the histopathological changes in the aortic wall. The combination of evolocumab and atorvastatin caused a more statistically significant reduction in TLRs at 10 weeks to 5.08±1.2 and intimal thickness to 121.79±5.3. IL-17, IL-1ß, ICAM, and VCAM were significantly (p<0.05) reduced by the combination, and the histopathological changes in the aortic wall were significantly improved. In conclusion, evolocumab delays the progression of atherosclerosis by modulating inflammatory pathways. [ABSTRACT FROM AUTHOR]

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane)bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis)associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll)like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, targeting PRRs and their new synthetic ligands may provide new therapeutic options for treating endometriosis. [ABSTRACT FROM AUTHOR]

To date, three Streptococcus parasuis strains, BS26, BS27, and NN1, have been isolated from the blood cultures of patients with peritonitis, pneumonia, and arthritis, indicating that S. parasuis is an emerging threat to susceptible people. There is thus an urgent need to further evaluate the pathogenesis of S. parasuis clinical strains in order to design efficient anti-inflammatory strategies. Our previous study demonstrated the capacity of S. parasuis clinical strains to enter the central nervous system (CNS) of infected mice. However, the characteristics and inflammatory mechanism of CNS infections caused by S. parasuis are still non-available. In the present study, we investigated the proportion and time of two clinical S. parasuis strains NN1 and BS26 infected mice that developed neurological symptoms. The characteristics of histopathological changes and the cerebral immune response in mice with neurological symptoms were analyzed. Furthermore, we evaluated the roles of microglia and astrocytes in the S. parasuis clinical strain-induced cerebral inflammation. Our data indicated that S. parasuis clinical strains possess a high potential to induce cerebral inflammation in susceptible people at the early phase of infection. Our study contributes to increasing the understanding of the pathogenicity of S. parasuis and the inflammatory mechanisms of the brain against infection caused by S. parasuis. [ABSTRACT FROM AUTHOR]