T-cell dysfunction has been shown to play an important role in the pathogenesis of Sjögren’s syndrome (SS). In recent studies, the increased expression of BMP6 has been reported to be related to SS. However, the roles that BMP6 plays in immune homeostasis in the development of SS as well as the downstream signals activated by BMP6 remain unclear. In this study, we investigated the effects and molecular mechanisms of BMP6 on naive CD4 + T cells, showing that BMP6 could upregulate interferon (IFN)–γ secretion from CD4 + T cells through a ceramide/nuclear factor–κB pathway, with no effect on T-cell activation or proliferation. Moreover, an in vivo study showed that anticeramide treatment (myriocin) for an SS animal model (NOD/LtJ mice) could significantly decrease the IFN-γ expression and Th1 frequency in the salivary glands and suppress the inflammation infiltration in salivary glands and maintain the salivary flow rates, both of which reflect SS-like symptoms. This study identifies a promising target that could effectively attenuate the abnormal state of CD4 + T cells and reverse the progression of SS.

Dendritic cells (DCs) can mediate inflammation-related bone resorption that is crucial in the development of periodontitis. Butyrate is a critical by-product of microbes with antibacterial and anti-inflammatory properties. Here, we found that butyrate inhibited the activation of lipopolysaccharide (LPS)–induced DCs and generation of inflammatory cytokines by DCs. Moreover, butyrate regulated glycolysis in LPS-induced DCs via the G-protein-coupled receptor/hypoxia-inducible factor–1α pathway. In addition, butyrate inhibited the maturation of CD11c + MHC-II + DCs in vivo, suppressing local inflammatory infiltration and ultimately alleviating bone resorption in a periodontitis model. Our results imply that butyrate suppresses the activation of LPS-induced DCs by modulating their metabolism, highlighting its potential as a therapeutic agent for inflammatory diseases.

The mechanisms underlying the chronic, progressive airways inflammation, remodelling and alveolar structural damage characteristic of human chronic obstructive pulmonary disease (COPD) remain unclear. In the present study, we address the hypothesis that these changes are at least in part mediated by respiratory epithelial alarmin (IL-33)-induced production of autoantibodies against airways epithelial cells. Mice immunized with homologous, syngeneic lung tissue lysate along with IL-33 administered directly to the respiratory tract or systemically produced IgG autoantibodies binding predominantly to their own alveolar type II epithelial cells, along with increased percentages of Tfh cells and B2 B-cells in their local, mediastinal lymph nodes. Consistent with its specificity for respiratory epithelial cells, this autoimmune inflammation was confined principally to the lung and not other organs such as the liver and kidney. Furthermore, the serum autoantibodies produced by the mice bound not only to murine, but also to human alveolar type II epithelial cells, suggesting specificity for common, cross-species determinants. Finally, concentrations of antibodies against both human and murine alveolar epithelial cells were significantly elevated in the serum of patients with COPD compared with those of control subjects. These data are consistent with the hypothesis that IL-33 contributes to the chronic, progressive airways obstruction, inflammation and alveolar destruction characteristic of phenotypes of COPD/emphysema through induction of autoantibodies against lung tissue, and particularly alveolar type II epithelial cells.

Abstract Background Cumulative evidences have shown that IL-6 in atrium might play an important role in the pathogenesis of postoperative AF (POAF) via activation of atrial fibrosis in patients undergoing CABG. However, whether atria produces IL-6 after the stimulation of CABG and its causal relationship with spontaneous POAF (sPOAF) and its specific pathways is still unclear. Purpose To test the hypothesis that atrium will produce IL-6 after CABG and causes sustained sPOAF (ssPOAF) through activating pSTAT3-mediated fibroblast proliferation. Methods To determine the causal relationship between IL-6 and sPOAF, IL-6−/− and wild type (WT) mice were both divided into three groups (10 mice/group): CABG group (NAI, mimic CABG), anti-inflammatory group (AI, mimic CABG with pericardial administration of methylprednisolone for 3 days via chest tube), and control group (anesthesia only). Mice were monitored for ssPOAF for 7 days using implanted telemetry device. Another two sets of mice, using the same models mentioned above, were euthanatized at 48th hours postoperatively. The atria of one set animals were excised and separated into pericardium (PC), pulmonary vein (PV), left atrium (LA), and right atrium (RA) and cultured for 4 hours. IL-6 levels in the supernatant were measured at 10 min and 4 hours of culture using ELISA test. The region producing the largest amount of IL-6 in the other set of animals was harvested for analyzing expressions of IL-6, pSTAT3/STAT3, connexin 43 and 40, fibroblast deposition, and collagen I and III. Path analysis was performed to determine the causal relationship of CABG induced IL-6 release, pSTAT3/fibroblast signaling, and the onset of ssPOAF. Results 40% NAI-WT mice developed ssPOAF (Figure 1A) which was completely protected in IL-6−/− and AI groups. IL-6 was produced by all 4 atrial regions at 4hrs after CABG stimulation with the LA producing the highest amount. Western blotting (Figure 1B), RT-CPR, Masson staining, and immunofluorescence all showed a significantly upregulation of IL-6, pSTAT3/STAT3, fibroblasts, collagen I and III, and downregulation of Cx40 an 43 in NAI-WT mice, but not in IL-6−/− and AI mice. IL-6 was colocalized with vimentin to a large extent in cytoplasm (Figure 1C). IL-6 had strong positive correlation with pSTAT3/STAT3, collagen I and III (all r>0.700, P<0.001), moderate and weak negative correlation with Cx40 and 43 (r=−0.505, P<0.001; r=−0.307, P=0.048, respectively). Path analysis (Figure 1D) revealed that every 1 unit increase in IL-6 upregulated a 0.589 unit increase in ssPOAF, which was mediated by pSTAT3/collagen indirectly and collagen I/ collagen III directly. Conclusion Our study, for the first time, to the best of our knowledge, established a novel pathophysiological role of IL-6/pSTAT3/fibroblast signaling in the pathogenesis of ssPOAF and demonstrated that inhibition of atrial IL-6 might be a potential novel sPOAF prevention strategy. Acknowledgement/Funding The National Natural Science Foundation (No.81170170)

Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.