TIR8 protects against nonalcoholic steatohepatitis by antagonizing lipotoxicity-induced PPARα downregulation and reducing the sensitivity of hepatocytes to LPS.

In up to one-third of nonalcoholic fatty liver disease (NAFLD) patients, simple steatosis progresses to its more severe form, nonalcoholic steatohepatitis (NASH), but the precise mechanisms underlying this transition are not fully understood. Toll/interleukin-1 receptor 8 (TIR8), a conventional innate immune regulator highly expressed in hepatic tissue, has shown potential for ameliorating various inflammation-related disorders. However, its role in NASH pathogenesis, especially its regulatory effects on lipid metabolism and inflammatory responses, is still unclear. Here, using a TIR8 knockout (TIR8KO) mouse model and mass spectrometry analyses, we found that TIR8KO mice displayed aggravated hepatic steatosis and inflammation, whereas TIR8 overexpression attenuated these adverse effects. Ectopic TIR8 expression counteracts free fatty acid (FFA)-induced PPARα inhibition and downstream signaling. A decrease in TIR8 levels in hepatocytes heightened lipopolysaccharide (LPS) sensitivity. Notably, FFA stimulation led to a direct interaction between TIR8 and proteasome subunit alpha type 4 (PSMA4), facilitating TIR8 degradation. These results revealed that TIR8 safeguards PPARα-regulated lipid metabolism and mitigates inflammation induced by external factors during NASH progression. Our study highlights TIR8 as a promising target for NASH therapy, indicating the potential of TIR8 agonists in treatment strategies.

IL-1R8 as Pathoimmunological Marker for Severity of Canine Chronic Enteropathy.

Chronic enteropathy (CE) is a severe multifactorial gastrointestinal disease that affects dogs and is driven by poorly characterized inflammatory pathways. Imbalance of pro-inflammatory response regulators, including IL-1R8, may be due to different factors, among which the infection with Helicobacteraceae is known to lead to a vicious circle in which excessive pro-inflammatory signaling and gastrointestinal injury reinforce each other and boost the disease. We investigated the expression of IL-1R8 in large intestine biopsies of dogs with or without clinical signs of CE and with previously assessed enterohepatic Helicobacter spp. colonization status by mean of quantitative real-time PCR. Our study revealed that IL-1R8 is downregulated in both acutely (p = 0.0074) and chronically (p = 0.0159) CE affected dogs compared to healthy controls. The data also showed that IL-1R8 expression tends to decrease with colonization by Helicobacter spp. Interestingly, a negative correlation was detected between the level of expression of IL-1R8 and the severity of macroscopic lesions identified by endoscopy and the crypt hyperplasia score. We further compared the expression levels between males and females and found no statistically significant difference between the two groups. No significant difference was observed in IL-1R8 expression profiles with the age of the animals either. Interestingly, an association was uncovered between IL-1R8 expression level and dog breed. Together, our data advance knowledge on gastrointestinal pathoimmunology in dogs and highlight the potential utilization of IL-1R8 as a diagnostic, prognostic and therapeutic biomarker for canine chronic enteropathy.

A negative feedback loop involving NF-κB/TIR8 regulates IL-1ß-induced epithelial- myofibroblast transdifferentiation in human tubular cells.

Renal tubular epithelial-myofibroblast transdifferentiation (EMT) plays a central role in the development of renal interstitial fibrosis (RIF). The profibrotic cytokine interleukin (IL)-1 and the IL-1 receptor (IL-1R) also participate in RIF development, and Toll/IL-1R 8 (TIR8), a member of the Toll-like receptor superfamily, has been identified as a negative regulator of IL-1R signaling. However, the functions of TIR8 in IL-1-induced RIF remain unknown. Here, human embryonic kidney epithelial cells (HKC) and unilateral ureteric obstruction (UUO)-induced RIF models on SD rats were used to investigate the functions of TIR8 involving IL-1ß-induced EMT. We showed that IL-1ß primarily triggers TIR8 expression by activating nuclear factor-κB (NF-κB) in HKC cells. Conversely, high levels of TIR8 in HKC cells repress IL-1ß-induced NF-κB activation and inhibit IL-1ß-induced EMT. Moreover, in vitro and in vivo findings revealed that TIR8 downregulation facilitated IL-1ß-induced NF-κB activation and contributed to TGF-ß1-mediated EMT in renal tubular epithelial cells. These results suggested that TIR8 exerts a protective role in IL-1ß-mediated EMT and potentially represents a new target for RIF treatment.

Staphylococcus aureus intra-mammary infection affects the expression pattern of IL-R8 in goat.

IL-1R8 is a member of Interleukin-1 receptor family acting as a negative regulator of inflammation reliant on ILRs and TLRs activation. IL-1R8 role has never been evaluated in acute bacterial mastitis. We first investigated IL-1R8 sequence conservation among different species and its pattern of expression in a wide panel of organs from healthy goats. Then, modulation of IL-1R8 during natural and experimental mammary infection was evaluated and compared in blood, milk and mammary tissues from healthy and Staphylococcus aureus infected goats. IL-1R8 has a highly conserved sequence among vertebrates. Goat IL-1R8 was ubiquitously expressed in epithelial and lymphoid tissues with highest levels in pancreas. IL-1R8 was down-regulated in epithelial mammary cells following S. aureus infection. Interestingly it was up-regulated in leukocytes infiltrating the infected mammary tissues suggesting that it could represent a target of S. aureus immune evasion.

Dendritic Cells Transduced with Single Immunoglobulin IL-1-Related Receptor Exhibit Immature Properties and Prolong Islet Allograft Survival.

Members of toll-like receptor-interleukin 1 receptor signaling [TLR/IL-1R (TIR)] superfamily mediate maturation of dendritic cells (DCs) and launch immune response in transplanted organs. In this study, we hypothesized that TIR8, also known as single immunoglobulin IL-1-related receptor (SIGIRR) molecule, refrain DCs from maturation and induce immune tolerance of transplanted organ. DCs were transduced with the recombinant adenovirus Ad5F35 to highly express SIGIRR (DC-SIGIRR), then injected to murine recipient before islet transplantation. It revealed that DCs transduced with SIGIRR had low expression of major histocompatibility and costimulatory molecules along with strong phagocytic ability in vitro assay. The data demonstrated that recipients treated with DC-SIGIRR had satisfying islet allograft function and long survival times, with an increase of Treg and reduction of Th17 in both spleen and draining lymph nodes in vivo. Therefore, genetic modification of SIGIRR inhibits DC activation and maturation, affects differentiation of T cell subsets, protects allograft biological function, and prolongs graft survival.

Characterization of a long isoform of IL-1R8 (TIR8/SIGIRR).

IL-1R8, also known as SIGIRR or TIR8, is a trans-membrane protein belonging to the IL-1 receptor family. The human gene includes ten exons, and alternative splicing can result in different isoforms. We, herein, characterized a longer isoform of IL-1R8 containing an in-frame additional sequence between the TIR domain and the C-terminal portion of the protein. IL-1R8 Long (IL-1R8L1) mRNA was specifically expressed and regulated in distinct cell lines, in a manner similar to the classic isoform. Overexpression of IL-1R8L1 resulted in the production of a corresponding protein that showed a pattern of cell localization similar to the classic isoform. An antibody directed against an IL-1R8L1 specific peptide, detected this novel isoform in different cell lines and tissues where this protein may complement the anti-inflammatory functions of classic IL-1R8.

Effects of Sodium Houttuyfonate on Pulmonary Inflammation in COPD Model Rats.

The anti-inflammatory effect of sodium houttuyfonate (SH), an herbal-originated drug that used in China clinically, was investigated on chronic obstructive pulmonary disease (COPD) inflammatory model rats induced by combination usage of cigarette smoke (CS) and lipopolysaccharide (LPS). The morphology of the lung tissue, the expression levels of cytokines in the bronchoalveolar lavage fluid (BALF), the protein levels of TLR4, NF-κB p65, and SIGIRR, and the mRNA levels of TLR4, MyD88, NF-κB p65, and SIGIRR in lung tissues were investigated, respectively. After treated by SH (24.3 mg/kg), the abnormal morphology changes of lung tissues in COPD rats, such as neutrophil infiltration and airway obstruction, were considerably alleviated, as well as both proinflammatory cytokines, TNF-α and IL-1ß, significantly decreased in BALF. The mRNA level of TLR4, MyD88, and NF-κB p65 and protein expression of TLR4 and NF-κB p65 in lung tissues decreased significantly after SH treatment, while both SIGIRR mRNA and protein levels increased significantly. These results suggest that SH markedly attenuated the pulmonary inflammation induced by CS and LPS and protected the lung tissue in COPD model rat. The anti-inflammatory effects were related to suppress the TLR4/NF-κB pathway dependent on MyD88. TIR8/SIGIRR might contribute to the protective effects of SH on pulmonary inflammation.

The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia.

Toll interleukin-1 receptor 8 (also known as TIR8, SIGIRR, or IL1R8) is a transmembrane receptor that inhibits inflammation. Accordingly, genetic inactivation of this protein exacerbates chronic inflammation and inflammation-associated tumors in mice. In particular, lack of TIR8 triggers leukemia progression in a mouse model of chronic lymphocytic leukemia (CLL), supporting its role as a novel tumor restrainer. The aim of this study was to measure the amount of TIR8 mRNA and protein in CLL cells, and to analyze its regulation of expression. Circulating leukemic cells expressed lower levels of TIR8 compared to normal B-lymphocytes. Treatment of CLL cells with Azacytidine restored higher levels of TIR8 suggesting that DNA methylation may be involved in modulating TIR8 expression, with implications for novel therapeutic strategies.

A protective role of IL-37 in cancer: a new hope for cancer patients.

IL-37 is a cytokine belonging to the IL-1 family. Although discovered in silico in 2000, significant advances in the understanding of its biology were made only in recent years. It is a member of the family with potent anti-inflammatory and immunosuppressive properties. It is produced as a precursor without a classic signal peptide. The precursor is cleaved into mature form in the cytoplasm by caspase-1. A small fraction of the cleaved IL-37 binds SMAD-3, translocates to the nucleus, and suppresses transcription of several proinflammatory genes. Both precursor and cleaved forms of IL-37 are secreted. They bind IL-18Rα chain (also used by IL-18 as a receptor subunit) and recruit Toll/IL-1R (TIR)-8 for transducing intracellular signaling. TIR-8 is a member of the IL-1 receptor family (IL-1RF) and was previously known as an orphan receptor. IL-37 suppresses activation of NF-κB and MAPK and activates Mer-PTEN-DOK pathway. It negatively regulates signaling mediated by TLR agonists, proinflammatory cytokines, and IL-1RF ligands. It also affects cell metabolism by inhibiting mTOR, GSK-3α/ß, and activating AMPK. Despite having the ability to dampen host's immune responses, the cytokine has been shown to exert antitumor effects, and it has been suggested that it may act as a prognostic marker in a variety of human cancers. Recent studies have suggested that IL-37 may represent a novel therapeutic tool in patients with cancer. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its anti-cancer effects, and suggest guidelines for future research.

Allergic airway inflammation: unravelling the relationship between IL-37, IL-18Rα and Tir8/SIGIRR.

The hallmarks of allergic bronchial asthma arise from chronic airway inflammation. Thus, elucidating the mechanisms regulating the maintenance of this chronic inflammatory response is key to understanding asthma pathogenesis. To date, it is not clear whether a predominance of proinflammatory factors or a reduced capacity of counterbalancing anti-inflammatory mediators is the pivotal factor predisposing individuals towards asthma development. The IL-1 cytokine family and its receptor systems comprise a variety of proinflammatory cytokines like IL-1ß and IL-18 and anti-inflammatory molecules such as the Toll/interleukin-1 receptor 8/single Ig IL-1 receptor (IL-R)-related molecule (Tir8/SIGIRR) and the recently established cytokine IL-37. This article reviews the functions of these IL-1 cytokine family members in the regulation of allergic airway inflammation and asthma as they have been assessed clinically, in vitro and in mouse models.

α-TLR2 antibody attenuates the Aß-mediated inflammatory response in microglia through enhanced expression of SIGIRR.

The immunoregulatory function of single-Ig-interleukin-1 related receptor (SIGIRR) is derived from its ability to constrain the inflammatory consequences of interleukin (IL)-1R and toll-like receptor (TLR)4 activation. This role extends to the brain, where SIGIRR deficiency increases the synaptic and cognitive dysfunction associated with IL-1R- and TLR4-mediated signalling. The current study set out to investigate the interaction between SIGIRR and TLR2 in brain tissue and the data demonstrate that the response to the TLR2 agonist, Pam3CysSK4 (Pam3Cys4), is enhanced in glial cells from SIGIRR(-/-) animals. Consistent with the view that ß-amyloid peptide (Aß) signals through activation of TLR2, the data also show that Aß-induced changes are exaggerated in glia from SIGIRR(-/-) animals. We report that microglia, rather than astrocytes, are the primary glial cell expressing both TLR2 and SIGIRR. While Aß increased TLR2 expression, it decreased SIGIRR expression in microglia. This was mimicked by direct activation of TLR2 with Pam3Cys4. We investigated the effect of an anti-TLR2 antibody (αTLR2) on the Aß-induced inflammatory responses and demonstrate that it prevented the expression and release of the pro-inflammatory cytokines TNFα and IL-6 from microglia. In addition, application of αTLR2 alleviated the Aß-mediated impairment in long-term potentiation (LTP) of hippocampal synaptic activity. The protective effects of αTLR2 were accompanied by an up-regulation in SIGIRR expression. We propose that a mechanism involving activation of PI3 kinase/Akt and the transcription factor peroxisome proliferator-activated receptor (PPAR)γ may facilitate this increase in SIGIRR. These findings highlight a novel role of SIGIRR as a negative regulator of TLR2-mediated inflammation in the brain.