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Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In airway epithelial cells, we also showed that the activation of Akt by a small molecule (SC79) enhances NO production and increases levels of nuclear Nrf2, which reduces IL-8 transcription during concomitant stimulation with Toll-like receptor (TLR) 5 agonist flagellin. We hypothesized that SC79's production of NO in macrophages might likewise enhance phagocytosis and reduce the transcription of some pro-inflammatory cytokines. Using live cell imaging of fluorescent biosensors and indicator dyes, we found that SC79 induces Akt activation, NO production, and downstream cGMP production in primary human M0 macrophages. This was accompanied by a reduction in IL-6, IL-8, and IL-12 production during concomitant stimulation with bacterial lipopolysaccharide, an agonist of pattern recognition receptors including TLR4. Pharmacological inhibitors suggested that this effect was dependent on Akt and Nrf2. Together, these data suggest that several macrophage immune pathways are regulated by SC79 via Akt. A small-molecule Akt activator may be useful in some infection settings, warranting future in vivo studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat stress is an important stressor in poultry husbandry with the rise in global temperature. Heat stress causes immune dysfunction and inflammatory responses in broiler chickens. Supplementation with plant extracts, which can be used to improve immune function and alleviate inflammatory response, can be an effective nutritional intervention. This study evaluated the effect of peppermint extract on the morphological changes and major pattern recognition receptors (PRRs) related to innate immunity and inflammatory response in the spleen of broiler chickens under chronic heat stress. Dietary peppermint extract inhibits chronic heat stress-induced activation of innate immunity and inflammatory response in the spleen of broiler chickens. Therefore, the supplementation with peppermint extract can be used to regulate innate immunity and inflammatory response in broiler chickens. The aim of this study was to investigate the effect of dietary peppermint extract (PE) on innate immunity and inflammatory responses in the spleen of broiler chickens under chronic heat stress. In order to further study the mechanism of the activation of innate immunity and inflammation induced by chronic heat stress and the regulatory effect of peppermint extract, we examined the spleen's histological change, the mRNA expression of major pattern recognition receptors (PRRs) (TLR2, TLR4, NOD1, MDA5 and DAI) and transcription factors (NF-κB, AP-1 and IRF3) and downstream inflammatory cytokines (IFN-α, IFN-β, IL-1β, IL-6 and TNF-α) of innate immune signaling pathways associated with heat stress in the spleen of broiler chickens. The results indicated that chronic heat stress damaged the spleen tissue. In addition, chronic heat stress induced the activation of innate immunity and inflammatory responses by increasing the mRNA expression of TLR2, TLR4 and DAI, mRNA expression of transcriptional factors (NF-κB, AP-1 and IRF3) and the concentration of downstream inflammatory cytokines in the spleen of broiler chickens. Dietary peppermint extract alleviated the damage of spleen tissue caused by chronic heat stress. In addition, peppermint extract reduced the mRNA expression of DAI, mRNA expression of transcriptional factors NF-κB, AP-1 and IRF3, and the concentration of inflammatory cytokines in the spleen of broiler chickens under chronic heat stress. In conclusion, dietary peppermint extract could have a beneficial effect on regulating inflammatory response and innate immunity via inhibiting the activation of NF-κB, AP-1 and IRF3 signaling pathways mediated by DAI in the spleen of broiler chickens induced by chronic heat stress. [ABSTRACT FROM AUTHOR]

Innate immunity plays an important role in host defense against microbial infections. It also participates in activation of acquired immunity through cytokine production and antigen presentation. Pattern recognition receptors such as Toll-like receptors and nucleotide oligomerization domain-like receptors sense invading pathogens and associated tissue injury, after which inflammatory mediators such as pro-inflammatory cytokines and nitric oxide are induced. Supersulfides are molecular species possessing catenated sulfur atoms such as persulfide and polysulfide moieties. They have recently been recognized as important regulators in cellular redox homeostasis by acting as potent antioxidants and nucleophiles. In addition, recent studies suggested that supersulfides are critically involved in the regulation of innate immune and inflammatory responses. In this review, we summarize current knowledge of the chemistry and biology of supersulfides, with particular attention to their roles in regulation of innate immune, and inflammatory responses. Studies with animal models of infection and inflammation demonstrated the potent anti-inflammatory functions of supersulfides such as blocking pro-inflammatory signaling cascades, reducing oxidative stresses, and inhibiting replication of microbial pathogens including severe acute respiratory syndrome coronavirus 2. Precise understanding of how supersulfides regulate innate immune responses is the necessary requirement for developing supersulfide-based diagnostic as well as therapeutic strategies against inflammatory disorders. [ABSTRACT FROM AUTHOR]

The mucociliary airway epithelium lines the human airways and is the primary site of host-environmental interactions in the lung. Following virus infection, airway epithelial cells initiate an innate immune response to suppress virus replication. Therefore, defining the virus-host interactions of the mucociliary airway epithelium is critical for understanding the mechanisms that regulate virus infection, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Non-human primates (NHP) are closely related to humans and provide a model to study human disease. However, ethical considerations and high costs can restrict the use of in vivo NHP models. Therefore, there is a need to develop in vitro NHP models of human respiratory virus infection that would allow for rapidly characterizing virus tropism and the suitability of specific NHP species to model human infection. Using the olive baboon (Papio anubis), we have developed methodologies for the isolation, in vitro expansion, cryopreservation, and mucociliary differentiation of primary fetal baboon tracheal epithelial cells (FBTECs). Furthermore, we demonstrate that in vitro differentiated FBTECs are permissive to SARS-CoV-2 infection and produce a potent host innate-immune response. In summary, we have developed an in vitro NHP model that provides a platform for the study of SARS-CoV-2 infection and other human respiratory viruses. [ABSTRACT FROM AUTHOR]

Extensive crosstalk exists between autophagy and innate immune signalling pathways. The stimuli that induce pattern recognition receptor (PRR)‐mediated innate immune signalling pathways, also upregulate autophagy. The purpose of this increased autophagy is to eliminate the stimuli and/or suppress the inflammatory pathways by targeted degradation of PRRs or intermediary proteins (termed 'inflammophagy'). By executing these functions, autophagy dampens excess inflammation triggered by the innate immune signalling pathways. Thus, autophagy helps in the maintenance of the body's innate immune homeostasis to protect from inflammatory and autoimmune diseases. Many autophagy‐dependent mechanisms that could control innate immune signalling have been studied over the last few years. However, still, the understanding is incomplete, and studies that are more systematic should be undertaken to delineate the mechanisms of inflammophagy. Here, we discuss the available knowledge of crosstalk between autophagy and PRR signalling pathways. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are evolutionarily conserved proteins of pattern recognition receptors (PRRs) and play a crucial role in innate immune systems recognition of conserved pathogen-related molecular samples (PAMPs). We identified and characterized TLR18 from Nile tilapia (Oreochromis niloticus), OnTLR18 , to elucidate its role in tissue expression patterns, modulation of gene expression after microbial challenge and TLR ligands, subcellular localization in fish and human cells, and the possible effectors TLR18 induces in a melanomacrophage-like cell line (tilapia head kidney (THK) cells). OnTLR18 expression was detected in all tissues examined, with the highest levels in the intestine and the lowest in the liver. OnTLR18 transcript was up-regulated in immune-related organs after bacterial and polyinosinic-polycytidylic acid (poly I:C) challenges and in the THK cells after lipopolysaccharide (LPS) stimulation. In transfected THK and human embryonic kidney (HEK) 293 cells, OnTLR18 localizes in the intracellular compartment. OnMyD88 and OnTRIF, but not OnTIRAP, were co-immunoprecipitated with OnTLR18, suggesting that the former two molecules are recruited by OnTLR18 as adaptors. The constitutively active form of OnTLR18 induced the production of pro-inflammatory cytokines, type I interferon (IFN), and antimicrobial peptides such as tumor necrosis factor α , interferon (IFN) d2.13 , tilapia piscidin (TP) 2, TP3, TP4, and hepcidin in THK cells. Our results suggest that OnTLR18 plays an important role in innate immunity through initiating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and IFN signaling pathways via OnMyD88 and OnTRIF and induces the production of various effectors in melanomacrophages. • OnTLR18 was cloned and characterized from Nile tilapia. • The expression of OnTLR18 was induced after bacterial injection and LPS stimulation. • OnTLR18 was localized to internal cellular compartments. • OnTLR18 recruited MyD88 and TRIF as adaptors. • Overexpression of truncated OnTLR18 promotes immune-related transcription factors. [ABSTRACT FROM AUTHOR]

Nucleotide-binding oligomerization domain (NOD)-like receptor 1 (NOD1) is a cytosolic pattern recognition receptor with a crucial role in the innate immune response of cells triggered by the presence of compounds such as gamma- d -glutamyl-meso-diaminopimelic acid (iE-DAP) present in the peptidoglycan of all gram-negative and certain gram-positive bacteria. Methionine (Met) and arginine (Arg) are functional AA with immunomodulatory properties. In the present study, we aimed to assess the effect of increased Met and Arg supply on mRNA abundance of genes associated with innate immune response, antioxidant function, and AA metabolism during iE-DAP challenge in bovine mammary epithelial cells (BMEC). Primary BMEC (n = 4 per treatment) were precultured in modified medium for 12 h with the following AA formulations: ideal profile of AA (control), increased Met supply (incMet), increased Arg supply (incArg), or increased supply of Met plus Arg (incMetArg). Subsequently, cells were challenged with or without iE-DAP (10 μg/mL) for 6 h. Data were analyzed as a 2 × 2 × 2 factorial using the MIXED procedure of SAS 9.4. Greater mRNA abundance of NOD1 , the antioxidant enzyme SOD1 , and AA transporters (SLC7A1 and SLC3A2) was observed in the incMet cells after iE-DAP stimulation. Although increased Met alone had no effect, incMetArg led to greater abundance of the inflammatory cytokine IL - 6, and the antioxidant enzyme GPX1 after iE-DAP stimulation. The increased Arg alone downregulated NOD1 after iE-DAP stimulation, coupled with a downregulation in the AA transporters mRNA abundance (SLC7A1 , SLC7A5 , SLC3A2 , and SLC38A9), and upregulation in GSS and KEAP1 mRNA abundance. Overall, the data indicated that increased supply of both Met and Arg in the culture medium were more effective in modulating the innate immune response and antioxidant capacity of BMEC during in vitro iE-DAP stimulation. [ABSTRACT FROM AUTHOR]

Metabolic diseases pose a tremendous health threat in both developed and developing countries. The pathophysiology of metabolic diseases is complex but has been shown to be closely associated with sterile inflammation, which is initiated by various danger molecules derived from metabolic overload, such as oxidized low-density lipoproteins (OxLDLs), free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), and cholesterol. These danger signals are sensed by pattern recognition receptors (PRRs) to activate proinflammatory signaling pathways and promote the release of proinflammatory mediators, leading to chronic low-grade inflammation. Although these harmful metabolic stimuli are generally regarded as damage-associated molecular patterns (DAMPs), a more specific definition and accurate classification for these DAMPs is still missing. In this opinion, we classify the harmful metabolic stimuli that can incite inflammatory responses and tissue damage via instigating PRRs as metabolism-associated molecular patterns (MAMPs), and we summarize their roles in metaflammation-mediated metabolic diseases. The pathogenesis and development of metabolic diseases are largely affected by metabolic inflammation, or 'metaflammation,' which is induced by metabolism-related danger signal molecules derived from metabolic overload. We define molecules derived from excess nutrients and their metabolites, capable of inciting inflammation via activating pattern recognition receptors (PRRs), as metabolism-associated molecular patterns (MAMPs), which are a subset of damage-associated molecular pattern (DAMPs) awaiting specific classification. MAMPs interact with PRRs to incite proinflammatory signaling pathways, such as NF-κB, MAPKs, and NLRP3 inflammasome pathways, driving the production of proinflammatory mediators and contributing to the initiation and progression of metabolic diseases. Targeting MAMPs and their downstream signaling molecules might be a promising strategy for developing therapeutic approaches to metabolic diseases. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS. [ABSTRACT FROM AUTHOR]

The innate immune system-based recognition of the pathogens or their PAMPs initiates the pro-inflammatory immune response required for the maintenance of the homeostasis. The dysregulation of this innate immune response causes several diseases including sepsis, cancer and autoimmunity. However, pattern recognition receptors (PRRs) including toll-like receptors (TLRs), complement receptors (CRs) and NLRs of inflammasomes regulate both these processes of recognition of pathogens/PAMPs and their clearance. These three major components of the innate immune arm were studied independently/separately for a long time. Various studies have now shown that they work in close association and their crosstalk is required for the pathogen clearance via regulating the process of phagocytosis and mounting the controlled but potent immune response. The loss or inhibition of any of the three components affects the other in a positive/negative manner that can affect the immune process required for efficient host defense. The present review is designed to provide the current information on their evolution like the requirement of TLRs and inflammasomes for pathogen recognition even in the presence of complements system and their interaction during various immunological processes including phagocytosis, autophagy and inflammatory immune response. [ABSTRACT FROM AUTHOR]

Background The brain death of a potential organ donor induces a systemic inflammatory response, resulting in inferior organ quality and function. Our study aimed to evaluate the effects of methylprednisolone (MPN) therapy on pattern recognition receptor (PRR) signaling in potential brain-dead (BD) kidney donors. Material and methods To evaluate the effects of MPN therapy on PRR signaling in BD kidney donors we performed a prospective randomized treatment-versus-control study. Fifty-one potential kidney donors were randomly divided into three groups: brain-dead donors (BDDs) who received 15 mg/kg/d of methylprednisolone (group T1, n = 17), BDDs who received 15 mg/kg/d of MPN at the time of filling consent for kidney donation and 100 mg/2 h until kidney harvest (group T2, n = 17), and normal donors as controls n = 17. Gene expression for Toll-like receptors (TLRs) 1–9 and their signaling pathway molecules including MYD88, TRIF, NF-KB1, IRAK, IRF3, and IRF7, as well as the inflammatory cytokines RANTES, IL-1β, TNF-α, IL-6, CXCL8, IL-18, IFN-α, and IFN-β was determined by PCR array. Due to the crucial role of TLRs 2 and 4 in pattern recognition, surface expression of these molecules was analyzed by flow cytometry. Plasma levels of inflammatory cytokines were measured by immunoassay. Finally, serum creatinine and cystatin C were measured in 100 kidney recipients one week and one, three, and six months after transplant. Result Polymerase chain reaction (PCR) array gene expression revealed greater expression of TLRs and signaling molecules in group T1 than in the controls. Surface expression of TLRs 2 and 4 were significantly greater in group T2 than in group T1 (P < .05). Plasma concentrations of inflammatory cytokines were significantly greater in group T1 than in controls (P < .05). The recipients that received kidneys from group T1 had significantly higher levels of creatinine and cystatin C than the recipients of kidneys from both group T1 and controls (P<0.05). Conclusion Administration of MPN to BDDs at specified periods until kidney harvest resulted in less systemic inflammation in the BDDs and improved renal function in kidney graft recipients compared with common MPN therapy. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILDs) include a number of diseases whose pathogenesis still is not fully understood. Idiopathic pulmonary fibrosis (IPF), the most frequent and severe form of ILDs is an epithelial-driven disease and the treatment consists of the use of antifibrotic agents. In the rest of ILDs an inflammation-driven pathway is believed to be the main pathogenetic mechanism and treatment consists of the use of immunomodulatory agents. In both groups it is believed that infection can play an important role in the development and progression of the diseases. The immune system can recognize exogenous threats or endogenous stress through specialized receptors namely pattern recognition receptors (PRRs) which in turn, initiate downstream signaling pathways to control immune responses. Recently, a link between PRRs and autophagy, a specialized biological process involved in maintaining cellular homeostasis but also involved in various immunologic processes, has been described. In this review, we focus on the reciprocal influences of PRRs with particular emphasis on Toll-like receptors and autophagy in modulating innate immune responses. [ABSTRACT FROM AUTHOR]

The innate immune system is the first line of defense against virus infection that triggers the expression of type I interferon (IFN) and proinflammatory cytokines. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns, resulting in the induction of innate immune responses. Viral RNA in endosomes is recognized by Toll-like receptors, and cytoplasmic viral RNA is recognized by RIG-I-like receptors. The host innate immune response is critical for protection against virus infection. However, it has been postulated that an excessive inflammatory response in the lung caused by the innate immune response is harmful to the host and is a cause of lethality during influenza A virus infection. Although the deletion of genes encoding PRRs or proinflammatory cytokines does not improve the mortality of mice infected with influenza A virus, a partial block of the innate immune response is successful in decreasing the mortality rate of mice without a loss of protection against virus infection. In addition, morbidity and mortality rates are influenced by other factors. For example, secondary bacterial infection increases the mortality rate in patients with influenza A virus and in animal models of the disease, and environmental factors, such as cigarette smoke and fine particles, also affect the innate immune response. In this review, we summarize recent findings related to the role of PRRs in innate immune response during respiratory viral infection. [ABSTRACT FROM AUTHOR]

Infections can cause a multitude of stresses on the host and microbe. To detect potential infections, the mammalian immune system utilizes several families of pattern recognition receptors, which survey the intracellular and extracellular environments for microbial products. Members of each receptor family induce antimicrobial effector responses, which include inflammatory cytokine or interferon expression, downregulation of protein synthesis, or host cell death. In this review, we discuss the benefits of each of these innate immune responses. We highlight how non-infectious bacteria and viruses typically activate a single family of receptors, which results in a predictable host response. Infections with virulent pathogens, in contrast, may activate receptors from distinct families. As each receptor family may induce responses that antagonize or synergize with the activities of another family, cell fate decisions during pathogenic encounters are unpredictable. Understanding the antagonistic antimicrobial activities of the innate immune system should provide insight into how cell fate decisions are made during infections and potentially during other environmental stresses. [ABSTRACT FROM AUTHOR]

Over the last decade it has emerged that inflammasome complexes provide a pivotal platform for the host innate immune system to respond to exogenous infectious microbes (viruses, bacteria, fungi) and non-infectious environmental agents (cigarette smoke, pollution), as well as endogenous “danger” signals. Upon the canonical activation of inflammasomes, a key effector function is to catalyze, via caspase-1, the maturation of the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which, in addition to chronic inflammatory responses have also been intimately linked to the inflammatory form of lytic cell death, pyroptosis. However, recent evidence suggests that inflammasomes exhibit marked pleiotropism beyond their canonical functions, whereby their activation can also influence a large number of cellular responses including proliferation, apoptosis, autophagy and metabolism. It is therefore not surprising that the dysregulated expression and/or activation of inflammasomes is increasingly implicated in numerous disease states, such as chronic auto-inflammatory and autoimmune disorders, metabolic syndrome, neurodegenerative and cardiovascular diseases, as well as cancer. In this review we will highlight recent advancements in our understanding of the transcriptional regulation of genes encoding inflammasome-associated innate immune receptors, and the impact on a variety of cellular responses during disease pathogenesis. [ABSTRACT FROM AUTHOR]

Corneal transparency may be compromised by viral infections causing corneal scarring, edema, and neovascularization. Ocular injury results from collateral damage induced by exacerbated immune response in corneal stroma. Myofibroblasts play a key role in this process by producing a disorganized extracellular matrix and inflammatory mediators. However, the immune response profile of myofibroblasts during viral infections is still under study. The aim of this work was to analyze the cytokine profile of human limbal myfibroblasts (HLMs) stimulated with the double-stranded RNA analog polyinosinic:polycytidylic acid (poly I:C) and to identify their signaling pathways. HLMs were isolated from cadaveric sclera-corneal rims and stimulated with poly I:C (10 μg/ml) for 12 h. The secretion of 36 cytokines was measured using the Human Cytokine Array Panel A. The secretion of IFN-β was quantified by ELISA. The expression of pattern recognition receptors (PRRs) such as TLR3, RIG-1 and MDA5 were analyzed by western blot assays. Furthermore, translocation of the nuclear factors NF-κB, IRF3, and IRF7 was assessed by fluorescence staining. In addition, the differentially expressed cytokines were analyzed using the Core Analysis Tool of the Ingenuity Pathway Analysis IPA software. HLMs stimulated with poly I:C increased (fold change > 2) the secretion of G-CSF, sTREM-1, CXCL1, CCL1, CXCL8, CXCL10, CXCL11, CCL2, CCL5, IL-13, IL-6, IL-1ra, and IFN-β compared with HLMs under basal conditions. Poly I:C stimulation also induced the expression of RIG-1 (p < 0.001), but the expression of TLR3 and MDA5 was unmodified. Finally, HLMs increased nuclear translocation of NF-κB, IRF3, and IRF7 after poly I:C stimulation. Bioinformatic analysis identified canonical signaling pathways associated with cell adhesion and diapedesis, chemokine signaling, and activation of IRFs by cytosolic pattern recognition receptors. These results demonstrate that HLMs secrete cytokines involved in immune cell activation and chemotaxis. The data suggest a key role for HLMs during viral infections in cornea and extend our knowledge about the signaling pathways they trigger. [ABSTRACT FROM AUTHOR]

Apparent redundancy is a recurrent theme in innate immunity in various domains including inflammatory cytokines, chemokines and pattern recognition receptors. While sharing core function, different mediators may subserve distinct functions related for instance to production and release (e.g. IL-1α versus IL-1β), predominantly local versus systemic function (e.g. PTX3 versus C-reactive protein) or fine tuning of innate and adaptive responses (chemokines). Based on hard-wired phagocyte recruitment and regulation by a wide spectrum of chemokines and conventional or atypical receptors, I argue that trafficking of phagocytic cells is a robust output of the chemokine system, resistant to genetic or environmental variation. In general, I speculate that the apparent overlap and redundancy observed in core functions represents an evolutionary strategy to preserve robust essential core outputs in the face of genetically or environmentally caused variation. [ABSTRACT FROM AUTHOR]

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development. [Display omitted] • Size and solubility of microbial ligands determine the immune response • Fungal mannans are directly drained to the LN to drive cell accrual via interferon release • Tuning mannan physical properties broadens epitope specificity of SARS-CoV-2 anti-Spike antibodies • An adjuvant formulation of mannan/alum induces heterosubtypic immunity against IAV The physical properties of fungal mannans determine their immunological activity, and modulating their physical form improves the adjuvant properties of these immune stimuli when included in vaccine formulations directed against respiratory viruses. [ABSTRACT FROM AUTHOR]

Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors. [ABSTRACT FROM AUTHOR]

• PRR expression on monocytes and neutrophils is diminished early after pediatric CPB. • Single dose methylprednisolone affects cytokine response but not PRR expression. • Intermediate monocytes exhibit higher levels of TLR2, TLR4 and CD64 after CPB. • TLR4 upregulation on intermediate monocytes correlates with poorer clinical course. Congenital heart surgery with cardiopulmonary bypass (CPB) initiates an immune response which frequently leads to organ dysfunction and a systemic inflammatory response. Complications associated with exacerbated immune responses may severely impact the postoperative recovery. The objective was to describe the characteristics of monocyte subpopulations and neutrophils at the level of pattern recognition receptors (PRR) and the cytokine response after CPB in infants. An observational cohort study was conducted between June 2016 and June 2017 of infants < 2 years of age, electively admitted for surgical correction of acyanotic congenital heart defects using CPB. Fourteen blood samples were collected sequentially and processed immediately during and up to 48 h following cardiac surgery for each patient. Flow cytometry analysis comprised monocytic and granulocytic surface expression of CD14, CD16, CD64, TLR2, TLR4 and Dectin-1 (CLEC7A). Monocyte subpopulations were further defined as classical (CD14++/CD16−), intermediate (CD14++/CD16+) and nonclassical (CD14+/CD16++) monocytes. Plasma concentrations of 14 cytokines, including G-CSF, GM-CSF, IL-1β, IL-1RA, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, TNF-α, IFN-γ, MIP-1β (CCL4) and TGF-β1, were measured using multiplex immunoassay for seven points in time. Samples from 21 infants (median age 7.4 months) were analyzed by flow cytometry and from 11 infants, cytokine concentrations were measured. Classical and intermediate monocytes showed first receptor upregulation with an increase in CD64 expression four hours post CPB. CD64–expression on intermediate monocytes almost tripled 48 h post CPB (p < 0.0001). TLR4 was only increased on intermediate monocytes, occurring 12 h post CPB (p = 0.0406) along with elevated TLR2 levels (p = 0.0002). TLR4 expression on intermediate monocytes correlated with vasoactive-inotropic score (r s = 0.642, p = 0.0017), duration of ventilation (r s = 0.485, p = 0.0259), highest serum creatinine (r s = 0.547, p = 0.0102), postsurgical transfusion (total volume per kg bodyweight) (r s = 0.469, p = 0.0321) and lowest mean arterial pressure (r s = -0.530, p = 0.0135). Concentrations of IL-10, MIP-1β, IL-8, G–CSF and IL-6 increased one hour post CPB. Methylprednisolone administration in six patients had no significant influence on the studied surface receptors but led to lower IL-8 and higher IL-10 plasma concentrations. Congenital heart surgery with CPB induces a systemic inflammatory process including cytokine response and changes in PRR expression. Intermediate monocytes feature specific inflammatory characteristics in the 48 h after pediatric CPB and TLR4 correlates with poorer clinical course, which might provide a potential diagnostic or even therapeutic target. [ABSTRACT FROM AUTHOR]