Wei Chen

C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4^–/– mice compared with WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naive CD4⁺ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interfered with the interaction between IL-6 and the IL-6 receptor (IL-6R) by directly competing to bind with IL-6R, leading to suppression of IL-6–induced activation of the STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor–signaling pathway, may be a potential therapeutic intervention for Th17-driven autoimmune diseases.

CTRP4, a secreted protein, plays an important role in protecting against sepsis and energy metabolism; however, its physiological functions in autoimmune disease remain unknown. In this study, we demonstrate that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4^−/− mice because of increased Th17 cell infiltration. In vitro, Ctrp4 deficiency enhanced the ability of naïve CD4⁺ T cells to differentiate into Th17 cells. Mechanistically, CTRP4 interfered with the binding of IL-6 to its receptor IL-6R by directly binding to IL-6R and suppressed the activation of STAT3-related pathways in response to IL-6. Furthermore, treatment of induced EAE mice with recombinant CTRP4 protein ameliorated the symptom. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor signaling pathway, may be a potential therapeutic intervention for multiple sclerosis.

Sepsis is an intractable clinical syndrome characterised by organ dysfunction when the body over‐responds to an infection. Sepsis has a high fatality rate and lacks effective treatment. Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved protein with high expression in the immune system and is related to cytosolic iron‐assembly and tumour suppression; however, research has been rarely conducted on its immune functions. Our study found that Fam96a^‐/‐ mice significantly resisted lesions during sepsis simulated by caecal ligation and puncture (CLP) or endotoxicosis models. After a challenge with lipopolysaccharide (LPS) or infection, Fam96a^‐/‐ mice exhibited less organ damage, longer survival, and better bacterial clearance with decreased levels of proinflammatory cytokines. While screening several subsets of immune cells, FAM96A‐expressing macrophages as the key cell type inhibited sepsis development. In vivo macrophage depletion or adoptive transfer experiments abrogated significant differences in the survival of sepsis between Fam96a^‐/‐ and wild‐type mice. Result of the bone‐marrow‐derived macrophage (BMDM) polarisation experiment indicated that FAM96A deficiency promotes the transformation of uncommitted monocytes/macrophages (M0) into M2 macrophages secreting less proinflammatory cytokines. FAM96A may mediate an immunometabolism shift—from oxidative phosphorylation (OXPHOS) to glycolysis—in macrophages during sepsis, mirrored by reactive oxygen species (ROS) and glucose uptake. These data demonstrate that FAM96A regulates inflammatory response and provide a novel genomic insight for sepsis treatment.

Despite the availability of antibiotics, current therapies to treat sepsis are still ineffective and many clinical trials aimed at neutralizing specific inflammatory cytokines have failed, suggesting the urgent need for new treatments. Using two models of LPS‐induced endotoxemia and cecal ligation and puncture (CLP)–induced sepsis, we investigated the effects of C1q/TNF‐related protein 4(CTRP4) on septic lethality and sepsis‐induced inflammation. The effects of CTRP4 on survival, inflammation, organ damage, and bacterial clearance were assessed. Here, we found that CTRP4 decreased the mortalities of mice and alleviated pathological lung injury in mice model. In vivo depletion and adoptive transfer studies showed CTRP4‐expressing macrophages as the key cell type inhibiting LPS‐induced septic shock. The mechanism associated with the CTRP4 deficiency involved promoting of TLR4 internalization and activation of downstream pathways that resulted in a lethal, prolonged proinflammatory cytokine storm. Treatment of macrophages with exogenous CTRP4 abrogated proinflammatory cytokine production. Our results showed CTRP4 regulates inflammatory response and could be a promising strategy to treat septic shock.

Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved intracellular protein that is involved in the maturation of the Fe/S protein, iron regulatory protein 1 (IRP1), and the mitochondria-related apoptosis of gastrointestinal stromal tumor cells. In this study, we used a mouse model of chemically induced colitis to investigate the physiological role of FAM96A in intestinal homeostasis and inflammation. At baseline, colons from Fam96a^−/− mice exhibited microbial dysbiosis, dysregulated epithelial cell turnover, an increased number of goblet cells, and disordered tight junctions with functional deficits affecting intestinal permeability. After cohousing, the differences between wild-type and Fam96a^−/− colons were abrogated, suggesting that FAM96A affects colonic epithelial cells in a microbiota-dependent manner. Fam96a deficiency in mice resulted in increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Importantly, the colitogenic activity of Fam96a^−/− intestinal microbiota was transferable to wild-type littermate mice via fecal microbial transplantation (FMT), leading to exacerbation of DSS-induced colitis. Taken together, our data indicate that FAM96A helps to maintain colonic homeostasis and protect against DSS-induced colitis by preventing gut microbial dysbiosis. This study used gene knockout animals to help to understand the in vivo effects of the Fam96a gene for the first time and provides new evidence regarding host–microbiota interactions.

Transmembrane 74 (TMEM74), a transmembrane protein as an autophagy inducer, has been proven to promote tumor cell (including cervical cancer cell line HeLa and hepatic carcinoma cell line HepG2) proliferation by triggering autophagy. To further determine the role of TMEM74 in cancer, we performed immunohistochemical staining on tissue array, and the results showed that TMEM74 exhibited significantly higher expression in several tumor types, especially in hepatocellular carcinoma, lung adenocarcinoma, and squamous carcinoma. Furthermore, higher expression level of TMEM74 in HepG2, A549, and H1299 cell lines were also detected compared with the corresponding normal cell lines, as detected by western blot. Meanwhile, further analysis showed that the levels of TMEM74 expression were closely correlated to survival period of patients—the higher expression of TMEM74 was correlated with shorter survival period. Moreover, the in vitro experiments showed that overexpression of TMEM74 led to accelerated proliferation of A549 and H1299 cells, while knockdown of TMEM74 reversed the outcomes. In conclusion, the results suggested that TMEM74 acts as an oncogene and a potential diagnostic marker and a therapeutic target for liver cancer and lung cancer.