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Acacetin, a flavonoid derived compound has been recognized for its diverse biological activities, such as anti-oxidative and anti-inflammatory effects. Acute lung injury (ALI) is a severe condition characterized by respiratory insufficiency and tissue damage, commonly triggered by pneumonia and severe sepsis. These conditions induce an inflammatory response via Toll-like receptor 4 (TLR4) signaling activation. This study explored acacetin's therapeutic potential against lipopolysaccharide (LPS) induced ALI in mice, focusing on its ability to modulate the NF-κB pathway via regulation of the Nod-like receptor family CARD domain containing 3 (NLRC3), a signal sensor that plays an important role in the regulation of inflammation and the maintenance of homeostasis. Our findings revealed that high-dose acacetin reduced the mortality rate of ALI mice, significantly ameliorated LPS-induced lung pathological changes, reduced lung edema, and decreased the expression of inflammatory mediators in lung tissues. This protective impact of acacetin appears to stem form its capacity to enhance NLRC3 expression, which, intern, can inhibit the activation of NF-κB and subsequently inhibit the production of inflammatory mediators. NLRC3 deficiency inhibits the protective effect of acacetin on ALI mice. Molecular docking also verified that acacetin tightly bound acacetin to NLRC3. Additionally, acacetin was found to influence macrophage recruitment dynamics via NLRC3, inhibiting the overactivation of NLRC3-NF-κB related pathways. Taken together, our results indicate that acacetin inhibited LPS-induced acute lung injury and macrophage overrecruitment to the lungs in mice by upregulating NLRC3. [ABSTRACT FROM AUTHOR]

NLRC3 belongs to the NOD-like receptor family and is recognized as a modulator of innate immune mechanisms. In this study, we firstly report that Ctenopharyngodon idelus NLRC3 (CiNLRC3) acts as a negative regulator in the antiviral immune response. Cinlrc3 is ubiquitously expressed across tested tissues, displaying particularly high expression in the intestine, spleen, gill and kidney. Notably, Cinlrc3 expression is markedly upregulated following grass carp reovirus (GCRV) infection both in vivo and in vitro. Functional assays reveal that the overexpression of CiNLRC3 hampers cellular antiviral responses, thereby facilitating viral replication. Conversely, the silencing of CiNLRC3 through siRNA transfection enhances these antiviral activities. Additionally, CiNLRC3 substantially diminishes the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated interferon (IFN) response in fish. Subsequent molecular investigations indicates that CiNLRC3 interacts with the RLR molecule node, IRF7 but not IRF3, by degrading the IRF7 protein in a proteasome-dependent manner. Furthermore, CiNLRC3 co-localizes with CiIRF7 in the cytoplasm and impedes the IRF7-induced IFN response, resulting in impairing IRF7-mediated antiviral immunity. Summarily, these findings underscore the critical inhibitory role of teleost NLRC3 in innate immunity, offering new perspectives on its regulatory functions and potential as a target for resistant breeding in fish. [ABSTRACT FROM AUTHOR]

Abstract Background Intestinal barrier is a dynamic interface between the body and the ingested food components, however, dietary components or xenobiotics could compromise intestinal integrity, causing health risks to the host. Gossypol, a toxic component in cottonseed meal (CSM), caused intestinal injury in fish or other monogastric animals. It has been demonstrated that probiotics administration benefits the intestinal barrier integrity, but the efficacy of probiotics in maintaining intestinal health when the host is exposed to gossypol remains unclear. Here, a strain (YC) affiliated to Pediococcus pentosaceus was isolated from the gut of Nile tilapia (Oreochromis niloticus) and its potential to repair gossypol-induced intestinal damage was evaluated. Results A total of 270 Nile tilapia (2.20 ± 0.02 g) were allotted in 3 groups with 3 tanks each and fed with 3 diets including CON (control diet), GOS (control diet containing 300 mg/kg gossypol) and GP (control diet containing 300 mg/kg gossypol and 108 colony-forming unit (CFU)/g P. pentosaceus YC), respectively. After 10 weeks, addition of P. pentosaceus YC restored growth retardation and intestinal injury induced by gossypol in Nile tilapia. Transcriptome analysis and siRNA interference experiments demonstrated that NOD-like receptors (NLR) family caspase recruitment domain (CARD) domain containing 3 (Nlrc3) inhibition might promote intestinal stem cell (ISC) proliferation, as well as maintaining gut barrier integrity. 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) revealed that addition of P. pentosaceus YC altered the composition of gut microbiota and increased the content of propionate in fish gut. In vitro studies on propionate’s function demonstrated that it suppressed nlrc3 expression and promoted wound healing in Caco-2 cell model. Conclusions The present study reveals that P. pentosaceus YC has the capacity to ameliorate intestinal barrier injury by modulating gut microbiota composition and elevating propionate level. This finding offers a promising strategy for the feed industry to incorporate cottonseed meal into fish feed formulations. Graphical Abstract

Objectives: Chronic obstructive pulmonary disease (COPD) is a medical condition defined by persistent airflow limitation and respiratory symptoms caused by airway and/or alveolar abnormalities. Pulmonary hypertension (PH) is one of the cardiovascular comorbidities associated with COPD. We investigated the correlation of NLRC3 levels in patients with COPD with prognostic and surrogate parameters of PH on echocardiography and examined whether it could be used to predict PH in this patient population. Methods: A total of 80 patients diagnosed with COPD and 40 healthy volunteers as the control group were included in the study. The COPD group was further divided into two subgroups according to the systolic pulmonary artery pressure (sPAP) as follows: sPAP<35 mmHg and sPAP≥35 mmHg. The enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of NLRC3 in peripheral blood. Results: Patients with sPAP≥35 mmHg had a lower mean NLRC3 level than those with sPAP<35 mmHg (P=0.006). The NLRC3 levels showed a significant negative correlation with sPAP, tricuspid regurgitation velocity, right atrium, and pulmonary artery diameter. For NLRC3, the cut-off value was found to be 271,486 ng/L, with a sensitivity of 74%, and specificity of 63% in distinguishing patients with sPAP≥35 mmHg from all patients with sPAP<35 mmHg. Conclusion: Our study results suggest that NLRC3 levels measured from peripheral blood are predictive of PH in patients with COPD. Although the exact function of NLRC3 in the lungs, COPD, and PH have not been completely understood, we believe these findings will serve as a model for future studies. [ABSTRACT FROM AUTHOR]

Background: Intestinal barrier is a dynamic interface between the body and the ingested food components, however, dietary components or xenobiotics could compromise intestinal integrity, causing health risks to the host. Gossypol, a toxic component in cottonseed meal (CSM), caused intestinal injury in fish or other monogastric animals. It has been demonstrated that probiotics administration benefits the intestinal barrier integrity, but the efficacy of probiotics in maintaining intestinal health when the host is exposed to gossypol remains unclear. Here, a strain (YC) affiliated to Pediococcus pentosaceus was isolated from the gut of Nile tilapia (Oreochromis niloticus) and its potential to repair gossypol-induced intestinal damage was evaluated. Results: A total of 270 Nile tilapia (2.20 ± 0.02 g) were allotted in 3 groups with 3 tanks each and fed with 3 diets including CON (control diet), GOS (control diet containing 300 mg/kg gossypol) and GP (control diet containing 300 mg/kg gossypol and 108 colony-forming unit (CFU)/g P. pentosaceus YC), respectively. After 10 weeks, addition of P. pentosaceus YC restored growth retardation and intestinal injury induced by gossypol in Nile tilapia. Transcriptome analysis and siRNA interference experiments demonstrated that NOD-like receptors (NLR) family caspase recruitment domain (CARD) domain containing 3 (Nlrc3) inhibition might promote intestinal stem cell (ISC) proliferation, as well as maintaining gut barrier integrity. 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) revealed that addition of P. pentosaceus YC altered the composition of gut microbiota and increased the content of propionate in fish gut. In vitro studies on propionate's function demonstrated that it suppressed nlrc3 expression and promoted wound healing in Caco-2 cell model. Conclusions: The present study reveals that P. pentosaceus YC has the capacity to ameliorate intestinal barrier injury by modulating gut microbiota composition and elevating propionate level. This finding offers a promising strategy for the feed industry to incorporate cottonseed meal into fish feed formulations. [ABSTRACT FROM AUTHOR]

While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis. [ABSTRACT FROM AUTHOR]

The autoimmune disorder systemic lupus erythematosus (SLE) is multifaceted, with limited therapeutic alternatives and detrimental side effects, particularly on bones and joints. This research endeavors to examine the curative potential and underlying mechanisms of in addressing SLE-associated bone and joint complications. Triptoquinone A and triptoquinone B, constituents of Tripterygium wilfordii polyglycoside tablets (TGTs), exhibit antioxidant and anti-inflammatory attributes; nonetheless, its function in SLE therapy remains elusive. This investigation delves into the role of oxidative stress in systemic lupus erythematosus (SLE) and probes the prospective remedial effects of triptoquinone A and triptoquinone B on inflammation and cartilage deterioration in SLE-affected joints. Employing bioinformatics analyses, differentially expressed genes (DEGs) and protein-protein interactions were discerned in SLE, rheumatoid arthritis (RA), and osteoarthritis (OA) datasets. Enrichment analyses unveiled shared genes implicated in immune system regulation and toll-like receptor signaling pathways, among others. Subsequent examination of triptoquinone A and triptoquinone B revealed their capacity to diminish NLRC3 expression in chondrocytes, resulting in decreased pro-inflammatory cytokine levels and cartilage degradation enzyme expression. Suppression of NLRC3 augmented the protective effects of triptoquinone A and B, implying that targeting NLRC3 may constitute a potential therapeutic strategy for inflammation and cartilage degeneration-associated conditions in SLE patients. Our discoveries indicate that triptoquinone A and triptoquinone B may impede SLE progression via the NLRC3 axis, offering potential benefits for SLE-affected bone and joint health. [ABSTRACT FROM AUTHOR]

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The innate immune system is the first line of defense for the host against any microbial attack. It can quickly identify microorganisms and produce an immune response, removing pathogenic microorganisms. However, a strong immune response might lead to excessive inflammation and even autoimmune diseases. NLRC3 is an important regulator of innate immune system homeostasis. It is a member of the anti-inflammatory NLR family and can inhibit excessive immune response in the body. In this review, we primarily focused on the current research progress on NLRC3 and its potential application. It can decrease the production of pro-inflammatory cytokines by inhibiting the NF-κB, MAK-ERK, PI3K-mTOR, IL-6/JAK2/STAT3, and cGAS-STING pathways. It also inhibits inflammatory responses by interfering with the assembly and activity of the NLRP3 inflammasome complexes. Additionally, NLRC3 can also reduce the functions of some antigen-presenting cells and their ability to activate and polarize CD4+ T cells into Th1 and Th17 subsets. NLRC3 is closely related to the development of tumors, infectious diseases, autoimmune diseases, and AD. These diseases might be treated effectively by regulating the expression of NLRC3. • NLRC3 is an important regulator of innate immune system homeostasis. • NLRC3 inhibits Several pro-inflammatory signaling pathways. • NLRC3 interferes with the assembly and activity of the NLRP3 inflammasome complexes. • NLRC3 weakens the function of antigen-presenting cells. • NLRC3 negatively regulates the immune response of CD4+ T cells. [ABSTRACT FROM AUTHOR]

NLRC3 is a member of the pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family, and plays a pivotal regulatory role in modulating the activation of immune cells. In macrophages, NLRC3 inhibits the activation of the NF-kB signaling pathway, the STING/TBK1 signaling pathway, and the formation of the inflammasome. In the context of T cells immune response, NLRC3 prevents the activation of T cells by regulating the function of dendritic cells and directly influencing the function of T cells. Different from other pattern recognition receptors, NLRC3 is more closely associated with regulatory activity than pathogens recognition, it influences the fates of cells, for example, prevents proliferation, promotes apoptosis and inhibits pyroptosis. These cellular functions regulated by NLRC3 are involved in the development processes of a variety of diseases, such as infectious disease, sterile inflammatory diseases, and cancer. However, its characteristics, function and regulatory mechanism in immune response and immune-related diseases have not been addressed fully. In this review, we elaborate the potential roles of NLRC3 from several different levels, include molecular mechanism, cellular functions in the immune-related diseases. [ABSTRACT FROM AUTHOR]

Cottonseed meal (CSM) and cottonseed protein concentrate (CPC) serve as protein alternatives to fish meal and soybean meal in the feed industry. However, the presence of gossypol residue in CSM and CPC can potentially trigger severe intestinal inflammation, thereby restricting the widespread utilization of these two protein sources. Probiotics are widely used to prevent or alleviate intestinal inflammation, but their efficacy in protecting fish against gossypol-induced enteritis remains uncertain. Here, the protective effect of Pediococcus pentosaceus , a strain isolated from the gut of Nile tilapia (Oreochromis niloticus), was evaluated. Three diets, control diet (CON), gossypol diet (GOS) and GOS supplemented with P. pentosaceus YC diet (GP), were used to feed Nile tilapia for 10 weeks. After the feeding trial, P. pentosaceus YC reduced the activity of myeloperoxidase (MPO) in the proximal intestine (PI) and distal intestine (DI). Following a 7-day exposure to Aeromonas hydrophila , the addition of P. pentosaceus YC was found to increase the survival rate of the fish. P. pentosaceus YC significantly inhibited the oxidative stress caused by gossypol, which was evidenced by lower reactive oxygen species (ROS) and malondialdehyde (MDA), as well as higher activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in PI and DI. Addition of P. pentosaceus YC significantly inhibited enteritis, with the lower expression of pro-inflammatory cytokines (il-1β , il-6 , il-8) and higher expression of anti-inflammatory cytokines tgf-β. RNA-seq analysis indicated that P. pentosaceus YC supplementation significantly inhibited nlrc3 and promoted nf-κb expression in PI and DI, and the siRNA interference experiment in vivo demonstrated that intestinal inflammation was mediated by NLRC3/NF-κB/IL-1β signaling pathway. Fecal bacteria transplantation experiment demonstrated that gut microbiota mediated the protective effect of P. pentosaceus YC. These findings offer valuable insights into the application of P. pentosaceus YC for alleviating gossypol-induced intestinal inflammation in fish. • P. pentosaceus YC addition maintained intestinal immunity and resisted A. hydrophila infection in gossypol-fed Nile tilapia. • P. pentosaceus YC addition relieved intestinal oxidative stress and inflammation in gossypol-fed Nile tilapia. • P. pentosaceus YC addition repressed intestinal inflammation by the inhibition of nlrc3 / nf-κb/il-1β signaling pathway in gossypol-fed Nile tilapia. • The altered gut microbiota mediated P. pentosaceus YC addition to alleviate oxidative stress and intestinal inflammation in gossypol-fed Nile tilapia. [ABSTRACT FROM AUTHOR]

NLRC3 is identified as a unique regulatory NLR involved in the modulation of cellular processes and inflammatory responses. In this study, a novel Nod like receptor C3 (NLRC3) was functionally characterized from seven band grouper in the context of nervous necrosis virus infection. The grouper NLRC3 is highly conserved and homologous with other vertebrate proteins with a NACHT domain and a C-terminal leucine-rich repeat (LRR) domain and an N-terminal CARD domain. Quantitative gene expression analysis revealed the highest mRNA levels of NLRC3 were in the brain and gill followed by the spleen and kidney following NNV infection. Overexpression of NLRC3 augmented the NNV replication kinetics in primary grouper brain cells. NLRC3 attenuated the interferon responses in the cells following NNV infection by impacting the TRAF6/NF-κB activity and exhibited reduced IFN sensitivity, ISRE promoter activity, and IFN pathway gene expression. In contrast, NLRC3 expression positively regulated the inflammasome response and pro-inflammatory gene expression during NNV infection. NLRC3 negatively regulates the PI3K–mTOR axis and activated the cellular autophagic response. Delineating the complexity of NLRC3 regulation of immune response in the primary grouper brain cells following NNV infection suggests that the protein acts as a virally manipulated host factor that negatively regulated the antiviral immune response to augment the NNV replication. • Grouper NLRC3 is highly conserved and homologous with other vertebrate NLRC3. • Highest expression of NLRC3 were in the brain and gill following NNV infection. • NLRC3 augmented the NNV replication kinetics in primary grouper brain cells. • NLRC3 attenuated the interferon responses in the cells following NNV infection by impacting the TRAF6/NF-κB activity. • NLRC3 negatively regulates the PI3K–mTOR axis and activated the cellular autophagic response. [ABSTRACT FROM AUTHOR]

Brain ischaemia is one of the leading causes of mortality and disability worldwide, and the damage caused by ischaemia not only induces primary damage but also that induced by ischaemia-reperfusion (I/R) injury. Multiple processes including inflammation and oxidative stress response play important roles in the development of brain ischaemia injury. Sevoflurane is a well-known volatile anaesthetic, and a recent study discovered the role of sevoflurane in suppression of the inflammation response process via inhibition of inflammatory infiltrates and production, maintaining the balance of cytokine responses, although the possible mechanism was not fully clear. NLRC3 is a member of the nucleotide-binding domain and leucine-rich repeat containing (NLR) family, and it has been regarded as a regulator of the inflammation process via the regulation of inflammasome formation, which is an initiator of inflammatory events. In the present study, we found that overexpression of NLRC3 reduced the apoptosis in a cellular model of ischaemia reperfusion, and the expression of pro-inflammatory cytokines was also decreased. Further study found that these effects might be mediated by the TRAF6/TLR4/NF-kB signalling pathway. Thus, we speculate that overexpression might enhance the effect of sevoflurane in inhibiting the inflammatory response process in an ischaemia reperfusion model, which might be a new therapeutic strategy.

Objective: The function and mechanism of NOD-like receptor family CARD-containing 3 (NLRC3) in psoriasis are not yet reported, even though it plays a crucial role in innate and adaptive immunity by inhibiting inflammation. Therefore, this research aims to investigate the role and mechanism of NLRC3 in psoriasis., Methods: HaCaT cells were induced to form a psoriasis cell model using 20 ng/mL IL-1β, 20 ng/mL IL-17A, 20 ng/mL IL-23, 50 ng/mL TNF-α, and 20 ng/mL oncostatin M. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were assessed to determine the proliferation, cell cycle, and apoptosis of HaCaT cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to measure the knockdown efficiency of NLRC3 and TRAF6 interfering RNA in HaCaT cells. Western blot analysis was performed to determine the expression levels of NLRC3, TRAF6, and proteins associated with the NF-κB signaling pathway. A mouse model of psoriasis-like dermatitis was established by evenly applying miquimod cream (62.5 mg/day) to both ears. Hematoxylin-eosin staining was used to measure ear thickness and inflammatory infiltrates in mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL were performed to detect cell proliferation and apoptosis. Interactions between NLRC3 and TRAF6 were predicted using the STRING database (https://cn.string-db.org/). Co-Immunoprecipitation was used to confirm interactions between NLRC3 and TRAF6. Ubiquitination of TRAF6 was assessed by Western blot., Results: Knockdown of NLRC3 expression promoted cell proliferation and inhibited cell apoptosis in HaCaT cells. In vivo, knockdown of NLRC3 expression significantly increased the infiltration of inflammatory cells and the proliferation of Ki-67 positive cells within mouse ear epidermis, while decreasing the number of apoptotic cells. NLRC3 interacted with TRAF6 and influenced its K63 ubiquitination level. Knockdown of TRAF6 expression resulted in increased cell proliferation and decreased cell apoptosis in HaCaT cells. In vivo, knockdown of TRAF6 expression led to a significant increase in inflammatory cell infiltration and Ki-67 positive cells in mouse ear epidermis, and a decrease in apoptotic cells. Inhibiting the NF-κB signaling pathway alleviated the progression of psoriasis, and interfering with TRAF6 activated the NF-κB signaling axis, contributing to the onset and advancement of psoriasis., Conclusion: NLRC3 affects the occurrence of psoriasis by regulating TRAF6 and influencing the NF-κB signaling axis-mediated inflammatory response. This finding offers a theoretical foundation for the treatment of psoriasis., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024. Published by Elsevier B.V.)

NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It’s role in HCC (hepatocellular carcinoma) is still unknown. In this study we firstly used the GEO (Gene Expression Omnibus) database and mIHC (multiple immunohistochemical analysis) with TMAs (tumor tissue microarrays) of HCC patients to evaluate NLRC3 levels. The tumor-bearing mouse models were also established with NLRC3 over-expressing and knock-down Hepal-6 cells to assess its effect. The data showed high NLRC3 expression was related with favorable overall survival (P=0.0386) and disease-free survival (P=0.0458). In addition, NLRC3 expression showed a positive correlation between CD8+ T cells infiltration. In vivo, NLRC3-overexpressing Hepal-6 tumors showed increased CD8+ T cell infiltration. NLRC3-knockdown Hepa1-6 tumors displayed decreased CD8+ T cell infiltration. At the same time, we also found the positive correlations between NLRC3 and CCL5 (C-C motif chemokine ligand 5, P

NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It's role in HCC (hepatocellular carcinoma) is still unknown. In this study we firstly used the GEO (Gene Expression Omnibus) database and mIHC (multiple immunohistochemical analysis) with TMAs (tumor tissue microarrays) of HCC patients to evaluate NLRC3 levels. The tumor-bearing mouse models were also established with NLRC3 over-expressing and knock-down Hepal-6 cells to assess its effect. The data showed high NLRC3 expression was related with favorable overall survival (P =0.0386) and disease-free survival (P =0.0458). In addition, NLRC3 expression showed a positive correlation between CD8+ T cells infiltration. In vivo , NLRC3-overexpressing Hepal-6 tumors showed increased CD8+ T cell infiltration. NLRC3-knockdown Hepa1-6 tumors displayed decreased CD8+ T cell infiltration. At the same time, we also found the positive correlations between NLRC3 and CCL5 (C-C motif chemokine ligand 5, P <0.0001, R2 = 0.2372) as well as CXCL9 (C-X-C motif chemokine ligand 9, P <0.0001, R2 = 0.2338) expressions. So NLRC3 high expression represents a novel predictor for positive survival outcomes in HCC patients, and NLRC3 is involved in CD8+ T cell infiltration, which is correlated with increased CCL5 and CXCL9 in TME (tumor microenvironment). This study implies that boosting NLRC3 is a promising treatment to enhance survival in HCC patients. [ABSTRACT FROM AUTHOR]

NLRs are important intracellular pattern recognition receptors and play an essential role in innate immunity for vertebrates. However, research on sturgeon NLRs is still scarce. In this study, the NLRC3-like gene from Siberian sturgeon (Acipenser baerii) (AbNLRC3-like) was cloned and characterized. The AbNLRC3-like full-length cDNA was composed of 3310 bp with a 166 bp of 5′-UTR, 2838 bp open reading frame (ORF) and 306 bp 3′-UTR, encoding 945 amino acids. Structural analysis of AbNLRC3-like showed the typical NLRs structure, including a central NACHT domain and a C-terminal 12 LRR motifs. Quantitative real-time PCR (qRT-PCR) analysis revealed that AbNLRC3-like was widely distributed in all tested tissues with a relatively high expression level in the mid-kidney, head-kidney and spleen. After Streptococcus iniae infection, the mRNA expression of AbNLRC3-like was significantly up-regulated at the pre-mortality period and the recovering period in valvula intestine, but it was significantly down-regulated around the mortality period in the duodenum and spleen. In splenic leukocyte, the mRNA expression of AbNLRC3-like was significantly induced by LPS, PGN and Poly(I:C). These results suggested that AbNLRC3-like may play a critical role in the immune response of Siberian sturgeon during pathogen challenge. To our best knowledge, this is the first report of the NLRC3 gene in sturgeon.

• Atypical NF-κB pathways cooperate with typical NF-κB activation pathways in regulating different aspects of innate and adaptive immune responses • Nlrp12, NLRC3, and NLRX1 have been identified as a negative regulator of inflammation but actually have two sides of inflammatory regulation. • Nlrp12, NLRC3, and NLRX1 play a role in the progression of a variety of tumors, and their regulation is a potential therapeutic modality. • Compiled the current potential therapeutic drugs with anti-inflammatory and anti-tumor effects targeting Nlrp12, NLRC3, and NLRX1. Nucleotide-binding and oligomerization structural domain (NOD)-like receptors (NLRs) play an important role in innate immunity as cytoplasmic pattern recognition receptors (PRRs). Over the past decade, considerable progress has been made in understanding the mechanisms by which NLR family members regulate immune system function, particularly the formation of inflammasome and downstream inflammatory signals. However, recent studies have shown that some members of the NLRs, including Nlrp12, NLRX1, and NLRC3, are important in the negative regulation of inflammatory signaling and are involved in the development of various diseases, including inflammatory diseases and cancer. Based on this, in this review, we first summarize the interactions between canonical and non-canonical nuclear factor-κB (NF-κB) signaling pathways that are mainly involved in NLRs, then highlight the mechanisms by which the above NLRs negatively regulate inflammatory signaling responses as well as their roles in tumor progression, and finally summarize the synthetic and natural derivatives with therapeutic effects on these NLRs, which are considered as potential therapeutic agents for overcoming inflammatory diseases. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3−/− mice to HTNV infection in order to establish a new model of HFRS. Nlrc3−/− mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3−/− mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3−/− mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics.

Hantaan virus (HTNV) infects humans and causes hemorrhagic fever with renal syndrome (HFRS). The development of well-characterized animal models of HFRS could accelerate the testing of vaccine candidates and therapeutic agents and provide a useful tool for studying the pathogenesis of HFRS. Because NLRC3 has multiple immunoregulatory roles, we investigated the susceptibility of Nlrc3−/− mice to HTNV infection in order to establish a new model of HFRS. Nlrc3−/− mice developed weight loss, renal hemorrhage, and tubule dilation after HTNV infection, recapitulating many clinical symptoms of human HFRS. Moreover, infected Nlrc3−/− mice showed higher viral loads in serum, spleen, and kidney than wild type C57BL/6 (WT) mice, and some of them manifested more hematological disorders and significant pathological changes within multiple organs than WT mice. Our results identify that HTNV infected Nlrc3−/− mice can develop clinical symptoms and pathological changes resembling patients with HFRS, suggesting a new model for studying the pathogenesis and testing of candidate vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Objective Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). Methods Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. Results The median age at disease onset was 1.2 years (range 0.2–16) and at the time of study recruitment was 14 years (range 3.5–17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. Conclusion WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs. [ABSTRACT FROM AUTHOR]

Few studies about nucleotide‐oligomerization domain‐like receptor subfamily C3 (NLRC3) in PASMCs have been conducted. This research aimed to investigate the role of NLRC3 on platelet‐derived growth factor (PDGF)‐induced proliferation of pulmonary artery smooth muscle cells (PASMCs) and its underlying mechanism. We found that the proliferation of PASMCs stimulated with PDGF decreased when phosphoinositide 3‐kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors pretreatment. Overexpression of NLRC3 inhibited the proliferation of PASMCs and the phosphorylation of PI3K and mTOR while knocking down NLRC3 reversed this effect. Targeted to PI3K or mTOR can also reverse the effect of NLRC3. Activation of PI3K increased the phosphorylation of mTOR while inhibition of PI3K reduced it. Our data suggest that PDGF can induce abnormal proliferation of PASMCs, and NLRC3 suppresses activation of the PI3K‐mTOR signaling thus inhibits PASMCs proliferation. These findings unveiled the effect of NLRC3 as an inhibitor of the PI3K‐mTOR pathway mediating protection against PASMCs proliferation. [ABSTRACT FROM AUTHOR]

Nucleotide‐binding domain, leucine‐rich repeat family with a caspase activation and recruitment domain 3 (NLRC3) participates in both immunity and cancer. The aim of this study was to determine the role of NLRC3 in human hepatocellular carcinoma (HCC) and the underlying mechanisms. We collected human liver tissues from nonalcoholic steatohepatitis (NASH), HCC, and adjacent normal tissues to characterize the pattern of NLRC3 expression by real‐time quantitative polymerase chain reaction and immunohistochemistry. Then, we used the HCC cell line, HuH‐7, transfected with small interfering RNA to silence the NLRC3 expression. 5‐Ethynyl‐2'‐deoxyuridine assay, scratch assay, and transwell invasion assay were used for assessing proliferation, migration, and invasion, respectively. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were conducted to assess cell apoptosis. The expression of NLRC3 was reduced in human HCC tissues, compared with normal liver and nonalcoholic steatohepatitis tissues. After knocking down of NLRC3, the proliferation, migration, and invasion were increased in HuH‐7 cells. And flow cytometry and TUNEL assay showed that HuH‐7 cell apoptosis was suppressed after NLRC3 knockdown. As for the underlying mechanisms, knockdown of NLRC3 in HuH‐7 cells was associated with the activation of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway under interleukin‐6 (IL‐6) stimulation. NLRC3 expression was downregulated in human HCC tissues. NLRC3 silencing in HuH‐7 cells can promote the proliferation, migration, and invasion of hepatocellular carcinoma cells. JAK2/STAT3 pathway activation induced by IL‐6 may be the underlying mechanism for HCC when NLRC3 expression is silenced. And the invasion of HuH‐7 cells was partially suppressed by the STAT3 specific inhibitor (cryptotanshinone). Therefore, NLRC3 may play a significant role in HCC and might be a therapeutic target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3‐kinase (PI3K) activation plays a critical role in the pulmonary vascular remodeling of pulmonary hypertension (PH). The nucleotide‐oligomerization domain (NOD)‐like receptor subfamily C3 (NLRC3) inhibits proliferation and inflammation via PI3K signaling in cancer. We previously showed NLRC3 was significantly reduced in PH patients, but the mechanism of function remains unclear. This study aimed to determine the potential role of NLRC3 in PH. We found that NLRC3 was downregulated in the pulmonary arteries of PH animal models and platelet‐derived growth factor‐BB (PDGF‐BB) stimulated pulmonary arterial smooth muscle cells (PASMCs). NLRC3 pretreatment reduced right ventricular systolic pressure, attenuated pulmonary vascular remodeling and RVHI, and ameliorated proliferation, migration, and inflammation. Monocrotaline (MCT)‐ and PDGF‐BB‐mediated PI3K activation were suppressed by NLRC3 pretreatment. 740Y‐P decreased the effect of NLRC3. Collectively, NLRC3 protected against MCT‐induced rat PH and PDGF‐BB‐induced PASMC proliferation, migration, and inflammation through a mechanism involving PI3K inhibition. NLRC3 may have a therapeutic effect on PH and provide a promising therapeutic strategy for PH. [ABSTRACT FROM AUTHOR]

Pasteurella multocida (P. multocida) is a significant zoonotic pathogen that has the ability to infect various animals. The inflammatory response caused by P. multocida and the negative regulatory mechanism are not completely understood. NOD-like receptor family CARD-containing 3 (NLRC3), an intracellular member of the NLR family, has been reported as a negative regulator in human. In this study, we aimed to explore the role of rabbit NLRC3 (rNLRC3) in P. multocida infection. Our findings revealed a negative correlation between the expression of rNLRC3 and inflammatory cytokines during P. multocida infection. The expression of rNLRC3 was reduced at the initial stage of P. multocida infection and then recovered. Furthermore, rNLRC3 significantly inhibited the activation of NF-κB by reducing phosphorylation and nuclear import of p65 in response to P. multocida infection. Additionally, overexpression of rNLRC3 attenuated the expression of pro-inflammatory cytokines IL-1β , IL-6 , IL-8 , and TNF-α. Moreover, we demonstrated that rNLRC3 diminished NF-κB activation by interacting with rTRAF4 and rTRAF6. Overexpression of rNLRC3 promoted P. multocida proliferation, while P. multocida proliferation decreased after knockdown of rNLRC3. We also found that the NACHT-LRR domain is a functional domain of rNLRC3 that regulates the NF-κB pathway. Our study suggests that rNLRC3 negatively regulates P. multocida -induced NF-κB signaling in rabbits. It can serve as a checkpoint to prevent dysfunctional inflammation. • rNLRC3 inhibit P. multocida -induced NF-κB. • NOD-LRR is functional domain. • rNLRC3 diminish NF-κB by interacting with rTRAF4 and 6. [ABSTRACT FROM AUTHOR]

The nucleotide-oligomerization domain (NOD)-like receptor subfamily C3 (NLRC3) is a newly discovered and incompletely characterized member of the NLR family which negatively regulates inflammatory responses. Inflammation is considered a critical pathogenesis in pulmonary hypertension (PH). This is the first study to hypothesize that NLRC3 is closely correlated with PH. Total of 43 PH patients who were diagnosed by right heart catheterization (RHC) and 20 age-matched healthy control subjects were included. Echocardiographic variables and blood biochemical parameters were tested. Results of World Health Organization functional class (WHOFC), Borg dyspnea score and 6-minute walk tests (6MWT) were recorded. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were measured from RHC. Serum NLRC3 concentrations were detected by ELISA. ROC curve analysis was used to evaluate the diagnostic value of NLRC3 concentrations in PH. We found that serum NLRC3 concentration was significantly decreased in PH compared to the healthy control group. Serum NLRC3 concentration correlated negatively with mPAP and PVR. In addition, a negative correlation between serum NLRC3 concentration and WHOFC were detected. We proposed a cut-off value of 2.897ng/mL for serum NLRC3 concentration which was able to predict PH with 88% sensitivity and 85% specificity. In conclusion, NLRC3 concentrations in PH were significantly decreased, suggesting that NLRC3 may potentially be a diagnosis index and represent a prognostic factor for PH patients. [ABSTRACT FROM AUTHOR]

Background Intestinal barrier dysfunctions are related to dysbacteriosis and chronic gut inflammation in type 2 diabetes. Although there is emerging evidence that the chronic gut inflammatory response is stimulated by nucleotide-binding oligomerization domain-like receptors (NLRs), the relationship and precise mechanism between NLRC3 and the colonic epithelial barrier remains largely elusive. Methods We investigated the function and mechanism of NLRC3 in the colonic tissues of diabetic mice and colonic epithelial cell lines. The regulatory mechanism between NLRC3, butyrate and tight junctions was elucidated via a transepithelial electrical resistance measurement, transmission electron microscopy, RNA interference and western blotting. Results In this study, we found that NLRC3 expression was decreased in the colonic tissues of diabetic mice. NLRC3 over-expression ameliorated colonic epithelial barrier integrity and up-regulated tight junction proteins in colonic epithelial cells. Knockdown of TRAF6 diminished NLRC3-induced ZO-1/occludin expression. In addition, we demonstrated that butyrate could stimulate NLRC3 expression in both diabetic mice and colonic epithelial cells. GPR43 on colonic epithelial cells is involved in the activation of NLRC3 induced by butyrate. Conclusion Our findings demonstrated that NLCR3 could ameliorate colonic epithelial barrier integrity in diabetes mellitus in a TRAF6-dependent manner, and NLCR3 was stimulated by butyrate via binding GPR43 on colonic epithelial cells. [ABSTRACT FROM AUTHOR]

Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3−/−) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH. • NLRC3 has been shown to be a potential marker of patients with pulmonary hypertension (PH), while its role in hypoxia-induced pulmonary hypertension is currently unclear. This is the first study to reveal the association between NLRC3 and hypoxia-induced PH. Moreover, the mechanism was different from that of other type of PH. NLRC3 acted not only on PASMCs but also on endothelial cells. Compared the effects of NLRC3 deletion between PASMCs and endothelial cells showed that NLRC3 played a major role in PASMCs in hypoxia-induced PH. [ABSTRACT FROM AUTHOR]

The mucosal surfaces are important for teleost as they are directly and continuously exposed to pathogen-rich aquatic environments. Scrutinization and recognition of the attached pathogens is the first crucial step of mucosal immunity initiation. Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are a large group of intracellular pathogen recognition receptors (PRRs) which play key roles in pathogen recognition and subsequent immune signaling pathways activation. In this study, we identified two NLRC3 genes (NLRC3a and NLRC3b), a subfamily of NLRs from turbot, and profiled their expression patterns in mucosal tissues following bacterial challenge. NLRC3a transcript contains an open reading frame (ORF) of 3405 bp that encodes a putative peptide of 1134 amino acids. While NLRC3b has an ORF of 3114 bp encoding 1037 amino acids. A caspase recruitment domain (CARD) at N-terminus characterized turbot NLRC3a, while NLRC3b seems to be unique to teleost, containing a fish specific NACHT associated (FISNA) domain and an extra B30.2 (PRY/SPRY) domain at C-terminus. In addition, NLRC3a and NLRC3b were detected in all the examined tissues, with the highest expression levels in kidney and blood, respectively. After bacteria challenge, expression levels of turbot NLRC3 genes were strongly induced in intestine rather than in skin and gill, while NLRC3a had relatively higher expression level than that of NLRC3b. Taken together, NLRC3 genes found in this study were the first NLR members identified in turbot. The different expression signatures of NLRC3a and NLRC3b in mucosal tissues following two bacterial infections indicated they probably have important roles in early response to bacterial infection in the first line of host defense system. [ABSTRACT FROM AUTHOR]

Nucleotide-binding domain, leucine-rich-repeat–containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication inNature, we identified NLRC3 as a negative regulator of PI3K–mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K–mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K–mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K–AKT targets FoxO3a and FoxO1 in the colon ofNlrc3−/−mice, suggesting that additional signaling pathways contribute to increased cellular proliferation. Moreover, NLRC3 suppresses colorectal tumorigenesis by promoting cellular apoptosis. Genes encoding intestinal stem cell markers BMI1 and OLFM4 are upregulated in the colon ofNlrc3−/−mice. Herein, we discuss recent findings and explore mechanisms through which NLRC3 regulates PI3K–mTOR signaling. Our studies highlight the therapeutic potential of modulating NLRC3 to prevent and treat cancer. [ABSTRACT FROM PUBLISHER]

Acute lung injury (ALI) progresses rapidly, is difficult to treat, and has a high fatality rate. The excessive inflammatory response is an important pathological mechanism of ALI. NLRC3 (NLR family CARD domain-containing 3), a non-inflammasome member of the NLR family, has been found that it could negatively regulates various biological pathways associated with inflammatory response, such as NF-κB (nuclear factor kappa B), PI3K (Phosphatidylinositol 3'-kinase)-Akt (protein kinase B)-mTOR (mammalian target of the rapamycin), and STING (stimulator of interferon genes) pathways, which are responsible for the progression of pulmonary inflammation and participate in regulating the pathological progression of ALI. However, the effects of NLRC3 in sepsis-induced pathological injury of lung tissue remain unclear. In this study, we aimed to investigate the potential effects of NLRC3 in the sepsis-induced ALI. To investigate whether NLRC3 participates in inhibiting the pulmonary inflammatory response of sepsis-induced ALI. Sepsis-induced ALI mice models were established by intrabronchial injection of lipopolysaccharide (LPS) or cecum ligation and puncture (CLP). The lentivirus with overexpression of NLRC3 (LV-NLRC3) and downregulation of NLRC3 (LV-NLRC3-RNAi) were transfected to LPS-induced ALI mice. The expression of NLRC3 was upregulated or downregulated in the lung tissue of sepsis-induced ALI mice. Transfection with NLRC3-overexpression lentivirus significantly decreased inflammatory response in the lung of LPS-induced ALI mice in contrast to the control group. By transfection with NLRC3-silencing lentivirus, the inflammatory response in LPS-induced ALI mice was aggravated. Our study provides evidence of the protective effect of NLRC3 in sepsis-induced ALI by inhibiting excessive inflammatory response of the lung tissue. Abbreviations Acute lung injury: ALI; intensive care units: ICU; lipopolysaccharide: LPS; acute respiratory distress syndrome: ARDS; bronchoalveolar lavage fluid: BALF; nucleotide-binding oligomerization domain-like receptors: NLRs; NLR family CARD domain containing 3: NLRC3; nuclear factor kappa B: NF-κB; tumor necrosis factor receptor-associated factor 6: TRAF6; Phosphatidylinositol 3'-kinase: PI3K; protein kinase B: Akt; mammalian target of the rapamycin: mTOR; stimulator of interferon genes: STING; TANK-binding kinase 1: TBK1; type I interferon: IFN-I; toll-like receptors: TLRs; tumor necrosis factor: TNF; interleukin: IL; NOD-like receptor protein 3: NLRP3; enhanced green fluorescent protein: EGFP; lentivirus: LV; phosphate-buffered saline: PBS; intrabronchial: i.t.; cecum ligation and puncture: CLP; wet/dry: W/D; Real time polymerase chain reaction: RT-PCR; enzyme-linked immunosorbent assay: ELISA; hematoxylin and eosin: H&E; radio immunoprecipitation assay: RIPA; sodium dodecyl sulfate polyacrylamide gel electrophoresis: SDS-PAGE; polyvinylidene fluoride: PVDF; glyceraldehyde 3-phosphate dehydrogenase: GAPDH; bovine serum albumin: BSA; Tris buffered saline containing Tween 20: TBST; standard deviation: SD; one-way analysis of variance: ANOVA; janus kinase 2: JAK2; activators of transcription 3: STAT3; pathogen associated molecular patterns: PAMPs; danger associated molecular patterns: DAMPs.

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3 , depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control. [Display omitted] • Obesity establishes an IFN-I-deprived tumor microenvironment and increases tumor burden • Myeloid cells from obese hosts are desensitized to STING stimulation • Saturated fatty acids inhibit the STING pathway by inducing NLRC3 • NLRC3 inhibits the immunogenicity of HNSCC in an IFN-I-dependent fashion The STING-type-I interferon pathway underpins immune surveillance against cancers. However, how metabolic comorbidity contributes to STING suppression is unclear. Heath et al. find that myeloid cells from obese hosts are desensitized to STING. Saturated fatty acids can inhibit STING by inducing NLRC3, dampening the immunogenicity of cancers. [ABSTRACT FROM AUTHOR]

Nod like receptors (NLRs) are a large group of cytoplasmic PRRs believed to play an important role in bacterial recognition in higher vertebrates. In this study, a novel Nod like receptor C3 (AsNLRC3) has been identified, cloned and characterised from Asian seabass, Lates calcarifer . The full-length AsNLRC3 transcript composed of a 4142 bp nucleic acid sequence encode for a protein of 1134 deduced amino acids. Three signature domains identified are conserved NACHT-domain, C-terminal LLR domain and N-terminal CARD effector domain. From the domain architecture and phylogenetic analysis, it was quite evident that AsNLRC3 is different from the NLR subfamily C of other teleosts. AsNLRC3 expressed in all the 11 tissues tested but highly expressed in tissues facing external environment such as gill, hindgut and midgut. The ontogenic expression profile of this receptor showed constitutive expression throughout the embryonic and larval developmental stages, which could be an innate immune strategy against different marine pathogens for larval survival. Infection with Vibrio alginolyticus and poly I:C induction showed an alteration of expression pattern in different tissues but did not show significant alteration in expression with Staphylococcus aureus infection. In vitro study in Asian seabass kidney cell line (SISK) stimulated with different ligands such as LPS, PGN and poly I:C showed considerable up-regulation at some of the time-points tested. These results suggest that AsNLRC3 can be a pivotal cytosolic innate immune receptor for recognizing wide array of pathogens in a euryhaline teleost model like Asian seabass in diverse environmental conditions. [ABSTRACT FROM AUTHOR]

Nucleotide oligomerization domain (NOD)-like receptor (NLR) family with a caspase activation and recruitment domain (CARD) containing 3 (NLRC3) protein is an important cytosolic pattern recognition receptor that negatively regulates innate immune response in mammals. Hitherto, the immunological significance of NLRC3 protein in fish remains largely uncharacterized. Here we identified and characterized a novel NLRC3 gene (named poNLRC3 ) implicated in regulation of fish innate immunity from Japanese flounder Paralichthys olivaceus . The poNLRC3 protein is a cytoplasmic protein with an undefined N-terminal domain, a NACHT domain, a fish-specific NACHT associated domain, six LRR motifs, and a C-terminal fish-specific PYR/SPYR (B30.2) domain but only shares less than 40% sequence identities with the known Japanese flounder NLRC proteins. poNLRC3 gene is ubiquitously expressed in all tested tissues and is dominantly expressed in the Japanese flounder head kidney macrophages (HKMs). We for the first time showed that poNLRC3 expression was significantly modulated by the stimulation of extracellular ATP, an important danger/damage-associated molecular pattern in activating innate immunity in P. olivaceus . Importantly, we revealed that poNLRC3 plays an important role in positively regulating ATP-induced IL-1beta and IL-6 gene expression, suggesting the involvement of poNLRC3 in extracellular ATP-mediated immune signaling. In addition, we showed that poNLRC3 mRNA expression was up-regulated in response to LPS and Edwardsiella tarda immune challenges. Finally, we showed that down-regulating the endogenous poNLRC3 expression with small interfering RNA significantly reduced LPS-induced proinflammatory cytokine gene expression in the Japanese flounder HKM cells. Altogether, we have identified a novel inducible fish NLR member, poNLRC3 , which is involved in extracellular ATP-mediated immune signaling and may positively regulate the LPS-induced innate immune response in the Japanese flounder HKM cells. [ABSTRACT FROM AUTHOR]

Cutaneous wound healing is a complicated process that is characterized by an initial inflammatory phase followed by a proliferative phase. NLRC3 plays important roles in innate immunity, inflammatory regulation and tumor cell growth. However, the function of NLRC3 in wound healing remains unclear. Here, we investigated the function of NLRC3 in acute cutaneous wound healing using Nlrc3 gene knockout (Nlrc3 −/− ) mice. Our results demonstrated that skin wound repair in Nlrc3 −/− mice was significantly accelerated compared with that in wild-type (WT) mice. NLRC3 deficiency promoted the inflammatory and proliferative phases in wounds enhanced the inflammatory response and increased re-epithelialization and granulation tissue formation, and these phenotypes were primarily ascribed to regulatory effects on p53 signaling. Mechanistically, we uncovered novel crosstalk between NLRC3 and p53 signaling and revealed that NLRC3 could mediate the ubiquitination and degradation of p53 in an Hsp90-dependent manner. In conclusion, our study suggests that NLRC3 is a critical negative regulator of the inflammatory response and cell proliferation during wound healing and that blocking NLRC3 may represent a potential approach for accelerating wound healing. [Display omitted] • The role of NLRC3 in skin wound healing was investigated. • NLRC3 deficiency accelerates skin wound healing in mice by promoting inflammation and the proliferation phase. • NLRC3 increases the stability of p53 in wounds by preventing its ubiquitination and degradation. • The interaction between NLRC3 and the chaperone protein Hsp90 prevents Hsp90/MDM2-mediated degradation of p53. [ABSTRACT FROM AUTHOR]

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Colorectal cancer (CRC) is the most common type of gastrointestinal tumor, but the available pharmacological treatment is insufficient. As a traditional Chinese medicine, the green walnut husks (QLY) exhibit anti-inflammatory, analgesic, anti-bacterial and anti-tumor effects. However, the effects and molecular mechanisms of QLY extracts on CRC were not yet made known., Objective: This study aims to provide efficient and low toxicity drugs for the treatment of CRC. The purpose of this study is to explore the anti-CRC effect and mechanism of QLY, providing preliminary data support for clinical research of QLY., Methods: Western blotting, Flow cytometry, immunofluorescence, Transwell, MTT, Cell proliferation assay, and xenograft model were used to perform the research., Results: In this study, the potential of QLY to inhibit the proliferation, migration invasion and induce apoptosis of the mouse colorectal cancer cell line CT26 in vitro was identified. The xenograft tumor model of CRC noted that QLY suppressed tumor growth without sacrificing body weight in mice. In addition, QLY-induced apoptosis in tumor cells through NLRC3/PI3K/AKT signaling pathway was revealed., Conclusion: QLY regulates the levels of mTOR, Bcl-2 and Bax by affecting the NLRC3/PI3K/AKT pathway to promote apoptosis of tumor cells, suppressing cell proliferation, invasion and migration, and subsequently preventing the progression of colon cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aberrant inflammation is an enabling characteristic of tumorigenesis. Thus, signaling cascades that alter inflammatory activation and resolution are of specific relevance to disease pathogenesis. Pattern recognition receptors (PRRs) are essential mediators of the host immune response and have emerged as critical elements affecting multiple facets of tumor pathobiology. The nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins are intracellular PRRs that sense microbial and non-microbial products. Members of the NLR family can be divided into functional sub-groups based on their ability to either positively or negatively regulate the host immune response. Recent studies have identified a novel sub-group of non-inflammasome forming NLRs that negatively regulate diverse biological pathways associated with both inflammation and tumorigenesis. Understanding the mechanisms underlying the function of these unique NLRs will assist in the rationale design of future therapeutic strategies targeting a wide spectrum of inflammatory diseases and cancer. Here, we will discuss recent findings associated with this novel NLR sub-group and mechanisms by which these PRRs may function to alter cancer pathogenesis. [ABSTRACT FROM AUTHOR]