Search

Myeloid-derived suppressor cells (MDSCs) are heterogeneous myeloid cell populations with immunosuppressive capacity, which contribute to immune regulation and tolerance induction. We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome (pSS) and mice with experimental SS (ESS). However, the molecular mechanisms underlying MDSCs dysfunction remain largely unclear. In this study, we first found that aryl hydrocarbon receptor (AhR) was highly expressed by human and murine polymorphonuclear MDSCs (PMN-MDSCs). Indole-3-propionic acid (IPA), a natural AhR ligand produced from dietary tryptophan, significantly promoted PMN-MDSC differentiation and their suppressive function on CD4+ T cells. In contrast, feeding tryptophan-free diet resulted in decreased PMN-MDSC response, a phenotype that could be reversed by IPA supplementation. The functional importance of PMN-MDSCs was demonstrated in ESS mice by cell-depletion approach. Notably, AhR expression was reduced in PMN-MDSCs during ESS development, while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells, which could be phenocopied by tryptophan-free diet. Interferon regulatory factor 4 (IRF4), a repressive transcription factor, was upregulated in PMN-MDSCs during ESS progression. Chromatin immunoprecipitation analysis revealed the binding capacity of IRF4 to the promoter region of AhR, while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses. Furthermore, dietary supplementation of IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function. Together, our results identify a novel function of AhR in modulating PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

The iron (Fe) metabolism plays important role in regulating systemic metabolism and obesity development. The Fe inside cells can form iron-sulfur (Fe-S) clusters, which are usually assembled into target proteins with the help of a conserved cluster assembly machinery. Family with sequence similarity 96A (FAM96A; also designated CIAO2A) is a cytosolic Fe-S assembly protein involved in the regulation of cellular Fe homeostasis. However, the biological function of FAM96A in vivo is still incompletely defined. Here, we tested the role of FAM96A in regulating organismal Fe metabolism, which is relevant to obesity and adipose tissue homeostasis. We found that in mice genetically lacking FAM96A globally, intracellular Fe homeostasis was interrupted in both white and brown adipocytes, but the systemic Fe level was normal. FAM96A deficiency led to adipocyte hypertrophy and organismal energy expenditure reduction even under nonobesogenic normal chow diet-fed conditions. Mechanistically, FAM96A deficiency promoted mechanistic target of rapamycin (mTOR) signaling in adipocytes, leading to an elevation of de novo lipogenesis and, therefore, fat mass accumulation. Furthermore, it also caused mitochondrial defects, including defects in mitochondrial number, ultrastructure, redox activity, and metabolic function in brown adipocytes, which are known to be critical for the control of energy balance. Moreover, adipocyte-selective FAM96A knockout partially phenocopied global FAM96A deficiency with adipocyte hypertrophy and organismal energy expenditure defects but the mice were resistant to high-fat diet-induced weight gain. Thus, FAM96A in adipocytes may autonomously act as a critical gatekeeper of organismal energy balance by coupling Fe metabolism to adipose tissue homeostasis.

The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1β release and pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.

It is considered that intestinal barrier dysfunction and systemic endotoxemia drive obesity and its related complications. However, what causes barrier dysfunction remains to be elucidated. Here, we showed that the gut microbiota from high-fat diet (HFD)-fed mice had impaired ability to degrade dietary flavonoids, and in correspondence, the microbial-derived flavonoid metabolite desaminotyrosine (DAT) was reduced. Supplementation of DAT in the drinking water was able to counter the HFD-induced body fat mass accumulation and body weight increment. This is correlated with the role of DAT in maintaining mucosal immune homeostasis to protect barrier integrity. DAT could attenuate dextran sodium sulfate (DSS)-induced mucosal inflammation in a type I interferon signal-dependent manner. Furthermore, intraperitoneal injection of DAT-protected mice from bacterial endotoxin-induced septic shock. Together, we identified DAT as a gut microbiota-derived anti-inflammatory metabolite that functions to modulate local and systemic immune homeostasis. Our data support the notion of dysbiosis being an important driving force of mucosal barrier dysfunction and systemic metabolic complications.

Recent progress indicates that the gut microbiota plays important role in regulating the host's glucose homeostasis. However, the mechanisms remain unclear. Here, we reported that one integral member of the murine gut microbiota, the protozoan

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.

ToxigenicIn this article, the mechanisms implying the probiotic effect againstAlthough many strains with ability against

Our current understanding of the host-microbiota interaction in the gut is dominated by studies focused primarily on prokaryotic bacterial communities. However, there is an underappreciated symbiotic eukaryotic protistic community that is an integral part of mammalian microbiota. How commensal protozoan bacteria might interact to form a stable microbial community remains poorly understood. Here, we describe a murine protistic commensal, phylogenetically assigned as Tritrichomonas musculis, whose colonization in the gut resulted in a reduction of gut bacterial abundance and diversity in wild-type C57BL/6 mice. Meanwhile, dietary nutrient and commensal bacteria also influenced the protozoan’s intestinal colonization and stability. While mice fed a normal chow diet had abundant T. musculis organisms, switching to a Western-type high-fat diet led to the diminishment of the protozoan from the gut. Supplementation of inulin as a dietary fiber to the high-fat diet partially restored the protozoan’s colonization. In addition, a cocktail of broad-spectrum antibiotics rendered permissive engraftment of T. musculis even under a high-fat, low-fiber diet. Furthermore, oral administration of Bifidobacterium spp. together with dietary supplementation of inulin in the high-fat diet impacted the protozoan’s intestinal engraftment in a bifidobacterial species-dependent manner. Overall, our study described an example of dietary-nutrient-dependent murine commensal protozoan-bacterium cross talk as an important modulator of the host intestinal microbiome. IMPORTANCE Like commensal bacteria, commensal protozoa are an integral part of the vertebrate intestinal microbiome. How protozoa integrate into a commensal bacterium-enriched ecosystem remains poorly studied. Here, using the murine commensal Tritrichomonas musculis as a proof of concept, we studied potential factors involved in shaping the intestinal protozoal-bacterial community. Understanding the rules by which microbes form a multispecies community is crucial to prevent or correct microbial community dysfunctions in order to promote the host’s health or to treat diseases.

The physiologic signals that regulate beige adipogenesis remain incompletely understood, especially those that limit browning and prevent overexpenditure of energy. In this study, the TNF family member cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT), also known as TNF super family protein 14 (TNFSF14), can inhibit adipose precursor differentiation into beige adipocytes. In acute cold stress, LIGHT deficiency in mice accelerated browning in the subcutaneous white adipose tissue (scWAT). Further experiments showed that LIGHT interacting with lymphotoxin-β receptor (LTβR) on adipose precursors blocked beige fat biogenesis. LTβR signals attenuated the JNK pathway, which contributed to their antibeiging effect. Blocking JNK activation using a small molecular inhibitor prevented cold-induced scWAT beiging. Furthermore, LIGHT/LTβR signals acted as an attenuator of white adipogenesis. LIGHT deficiency in mice promoted obesity during high-fat diet feeding. These findings identify the LIGHT axis as a regulator of adipose tissue homeostasis and suggest that LIGHT signaling functions as a mechanism to divert energy in favor of immune activation.-Kou, Y., Liu, Q., Liu, W., Sun, H., Liang, M., Kong, F., Zhang, B., Wei, Y., Liu, Z., Wang, Y. LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

In this study, the structural characterization of Sphallerocarpus gracilis polysaccharide (SGP) and its hypoglycaemic activities are reported for the first time. SGP, which has a weight average molar mass (Mw) of 7.413×105, was isolated from Sphallerocarpus gracilis and purified by ion-exchange chromatography. The polysaccharide is composed of rhamnose, arabinose, mannose, glucose and galactose, with the molar ratio of 4.12: 8.99: 5.45: 65.94: 15.50. The mechanism underlying the hypoglycaemic effect of SGP was evaluated. Experimental results showed that SGP protected pancreatic β-cells from alloxan damage by several possible mechanisms, including: (1) repairing free radical damage; (2) reducing the apoptosis of pancreatic β-cells by inhibiting the activities of caspase-3 and bax, and enhancing the activity of bcl-2; (3) stimulating insulin secretion and upregulating the pancreatic and duodenal homeobox 1 gene and the insulin gene and the pancreatic in pancreatic β-cells. The results obtained in this study suggest that SGP may be a promising therapeutic agent in the treatment of diabetes mellitus.

Background Clostridium difficile (C. difficile) is a main cause of antibiotic-associated diarrhoea in humans. Several studies have been performed to reveal the prevalence rate of C. difficile in cats and dogs. However, little is known about the epidemiology of C. difficile in healthy pets in China. This study aimed to assess the burden of C. difficile shedding by healthy dogs and cats in China. Furthermore, the genetic diversity and antimicrobial susceptibility patterns of the recovered isolates were determined. Methods A total of 175 faecal samples were collected from 146 healthy dogs and 29 cats. C. difficile strains were isolated and identified from the feces of these pets. The characterized C. difficile strains were typed by multilocus sequence typing (MLST), and the MICs of the isolates were determined against ampicillin, clindamycin, tetracycline, moxifloxacin, chloramphenicol, cefoxitin, metronidazole and vancomycin by the agar dilution method. Results Overall, 3 faecal samples (1.7%) were C. difficile culture positive. One sample (0.7%) from a dog was C. difficile culture positive, while two cats (7.0%) yielded positive cultures. The prevalence rate differed significantly between cats and dogs. These isolates were typed into 3 MLST genotypes and were susceptible to chloramphenicol, tetracycline, metronidazole and moxifloxacin and resistant to ampicillin, clindamycin and cefoxitin. Notably, one strain, D141–1, which was resistant to three kinds of antibiotics and carried toxin genes, was recovered in the faeces of a healthy dog. Conclusion Our results suggest that common pets may be a source of pathogenic C. difficile, indicating that household transmission of C. difficile from pets to humans can not be excluded.

The heterotrimeric G protein subunit Gsα couples receptors to activate adenylyl cyclase and is required for the intracellular cAMP response and protein kinase A (PKA) activation. Gsα is ubiquitously expressed in many cell types; however, the role of Gsα in neural crest cells (NCCs) remains unclear. Here we report that NCCs-specific Gsα knockout mice die within hours after birth and exhibit dramatic craniofacial malformations, including hypoplastic maxilla and mandible, cleft palate and craniofacial skeleton defects. Histological and anatomical analysis reveal that the cleft palate in Gsα knockout mice is a secondary defect resulting from craniofacial skeleton deficiencies. In Gsα knockout mice, the morphologies of NCCs-derived cranial nerves are normal, but the development of dorsal root and sympathetic ganglia are impaired. Furthermore, loss of Gsα in NCCs does not affect cranial NCCs migration or cell proliferation, but significantly accelerate osteochondrogenic differentiation. Taken together, our study suggests that Gsα is required for neural crest cells-derived craniofacial development.

Asymmetric cell division, which plays fundamental roles in generating cell diversity during development, requires elaborate interactions between extrinsic cues and intrinsic cues. However, the precise nature of this type of interaction and its involving signaling mechanisms are poorly understood. Here, we demonstrate that Gαs is present in the proliferative region of ventricular zone in mouse developing neocortex and co-localizes with intrinsic cell fate determinant protein Numb in dividing apical progenitors. Targeted ablation of Gαs subunit in the cortical progenitor causes an alteration from asymmetric to symmetric cell division, consequently leading to increased progenitor proliferation. Mechanistically, we show that Gαs deletion significantly reduces Numb expression and activates notch signaling. Therefore, these results reveal a novel role of Gαs in control of neural progenitor asymmetric cell division via suppressing Numb mediated Notch signaling inhibition.