Xing C.,Chinese Institute of Basic Medical Sciences |
Ma N.,Chinese Institute of Basic Medical Sciences |
Ma N.,Jilin University |
Xiao H.,Chinese Institute of Basic Medical Sciences |
And 11 more authors.
Journal of Leukocyte Biology
This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19+CD5+CD1dhigh B cell subset that may play a critical role in the maintenance of immune homeostasis. Indeed, this population was identified in the murine thymus, and furthermore, when cocultured with CD4+T cells, this population of B cells supported the maintenance of CD4+Foxp3+Tregsin vitro, in part, via the CD5–CD72 interaction. Mice homozygous for Cd19Cre(CD19–/–) express B cells with impaired signaling and humoral responses. Strikingly, CD19–/–mice produce fewer CD4+Foxp3+Tregsand a greater percentage of CD4+CD8–and CD4–CD8+T cells. Consistent with these results, transfer of thymic CD19+CD5+CD1dhiB cells into CD19–/–mice resulted in significantly up-regulated numbers of CD4+Foxp3+Tregswith a concomitant reduction in CD4+CD8–and CD4–CD8+T cell populations in the thymus, spleen, and LNs but not in theBMof recipient mice. In addition, thymic CD19+CD5+CD1dhi B cells significantly suppressed autoimmune responses in lupus-likemice via up-regulation of CD4+Foxp3+ Tregsand IL-10-producing Bregs. This study suggests that thymic CD19+CD5+CD1dhiIL-10+Bregsplay a critical role in the maintenance of immune homeostasis. © Society for Leukocyte Biology. Source
Liu Y.,Chinese Institute of Basic Medical Sciences |
Liu Y.,State Key Laboratory of Toxicology and Medical Countermeasures |
Mu R.,Peking University |
Gao Y.-P.,Chinese Institute of Basic Medical Sciences |
And 16 more authors.
Cell Host and Microbe
Human cytomegalovirus (hCMV), a ubiquitous beta-herpesvirus, has been associated with several autoimmune diseases. However, the direct role of hCMV in inducing autoimmune disorders remains unclear. Here we report the identification of an autoantibody that recognizes a group of peptides with a conserved motif matching the Pp150 protein of hCMV (anti-Pp150) and is shared among patients with various autoimmune diseases. Anti-Pp150 also recognizes the single-pass membrane protein CIP2A and induces the death of CD56bright NK cells, a natural killer cell subset whose expansion is correlated with autoimmune disease. Consistent with this finding, the percentage of circulating CD56bright NK cells is reduced in patients with several autoimmune diseases and negatively correlates with anti-Pp150 concentration. CD56bright NK cell death occurs via both antibody- and complement-dependent cytotoxicity. Our findings reveal that a shared hCMV-induced autoantibody is involved in the decrease of CD56bright NK cells and may thus contribute to the onset of autoimmune disorders. © 2016 Elsevier Inc. Source
Jiang X.,Chinese Institute of Basic Medical Sciences |
Jiang X.,State Key Laboratory of Toxicology and Medical Countermeasures |
Jiang X.,Beijing Institute of Transfusion Medicine |
Yu J.,Henan University |
And 15 more authors.
Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy. © 2015 Elsevier Inc. Source
Ning C.,Chinese Institute of Basic Medical Sciences |
Ning C.,State Key Laboratory of Toxicology and Medical Countermeasures |
Li Y.-Y.,Henan University |
Wang Y.,Chinese Institute of Basic Medical Sciences |
And 19 more authors.
Colitis-associated colorectal cancer (CAC) is the most serious complication of inflammatory bowel disease (IBD). Excessive complement activation has been shown to be involved in the pathogenesis of IBD. However, its role in the development of CAC is largely unknown. Here, using a CAC model induced by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS), we demonstrated that complement activation was required for CAC pathogenesis. Deficiency in key components of complement (e.g., C3, C5, or C5a receptor) rendered tumor repression in mice subjected to AOM/DSS. Mechanistic investigation revealed that complement ablation dramatically reduced proinflammatory cytokine interleukin (IL)-1β levels in the colonic tissues that was mainly produced by infiltrating neutrophils. IL-1β promoted colon carcinogenesis by eliciting IL-17 response in intestinal myeloid cells. Furthermore, complement-activation product C5a represented a potent inducer for IL-1β in neutrophil, accounting for downregulation of IL-1β levels in the employed complement-deficient mice. Overall, our study proposes a protumorigenic role of complement in inflammation-related colorectal cancer and that the therapeutic strategies targeting complement may be beneficial for the treatment of CAC in clinic. Source
Zhuang X.-M.,Beijing Institute of Pharmacology and Toxicology |
Zhuang X.-M.,State Key Laboratory of Toxicology and Medical Countermeasures |
Wei X.,Beijing Institute of Pharmacology and Toxicology |
Wei X.,State Key Laboratory of Toxicology and Medical Countermeasures |
And 11 more authors.
Organophosphorus pesticides are the most widely used pesticides in modern agricultural systems to ensure good harvests. Isocarbophos (ICP), with a potent acetylcholinesterase inhibitory effect is widely utilized to control a variety of leaf-eating and soil insects. However, the characteristics of the bioactivation and detoxification of ICP in humans remain unclear. In this study, the oxidative metabolism, esterase hydrolysis, and chiral inversion of ICP in human liver microsomes (HLMs) were investigated with the aid of a stereoselective LC/MS/MS method. The depletion of ICP in HLMs was faster in the absence of carboxylesterase inhibitor (BNPP) than in the presence of NADPH and BNPP, with t1/2 of 5.2 and 90 min, respectively. Carboxylesterase was found to be responsible for the hydrolysis of ICP, the major metabolic pathway. CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19 were all involved in the secondary metabolism pathway of desulfuration of ICP. Flavin-containing monooxygenase (FMO) did not contribute to the clearance of ICP. The hydrolysis and desulfuration of (±)ICP, (+)ICP, and (-)ICP in HLMs follow Michaelis-Menten kinetics. Individual enantiomers of ICP and its oxidative desulfuration metabolite isocarbophos oxon (ICPO) were found to be inhibitors of acetylcholinesterases at different extents. For example, (±)ICPO is more potent than ICP (IC50 0.031μM vs. 192μM), whereas (+)ICPO is more potent than (-)ICPO (IC50 0.017μM vs. 1.55μM). Given the finding of rapid hydrolysis of ICP and low abundance of oxidative metabolites presence in human liver, the current study highlights that human liver has a greater capacity for detoxification of ICP. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. Source