ABSTRACT
Gut microbiota-derived extracellular vesicles (mEVs) are reported to regulate inflammatory response by delivering bacterial products into host cells. The complement receptor of the immunoglobulin superfamily macrophages (CRIg+ Mφ) could clear invading bacteria and their derivatives. Here, we investigate the role of CRIg+ Mφ and the mechanism by which mEVs regulate intestinal inflammation. We found that it is exacerbated in IBD patients and colitis mice by mEVs' leakage from disturbed gut microbiota, enriching microbial DNA in the intestinal mucosa. CRIg+ Mφ significantly decrease in IBD patients, allowing the spread of mEVs into the mucosa. The microbial DNA within mEVs is the key trigger for inflammation and barrier function damage. The cGAS/STING pathway is crucial in mEVs-mediated inflammatory injury. Blocking cGAS/STING signaling effectively alleviates inflammation caused by mEVs leakage and CRIg+ Mφ deficiency. Microbial DNA-containing mEVs, along with CRIg+ Mφ deficiency, stimulate inflammation in IBD, with the cGAS/STING pathway playing a crucial role.
Subject(s)
DNA, Bacterial , Extracellular Vesicles , Gastrointestinal Microbiome , Inflammation , Inflammatory Bowel Diseases , Intestinal Mucosa , Macrophages , Membrane Proteins , Nucleotidyltransferases , Extracellular Vesicles/metabolism , Extracellular Vesicles/immunology , Animals , Mice , Macrophages/immunology , Macrophages/microbiology , Macrophages/metabolism , Inflammatory Bowel Diseases/microbiology , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/immunology , Humans , Membrane Proteins/metabolism , Membrane Proteins/genetics , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Intestinal Mucosa/microbiology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestinal Mucosa/immunology , Inflammation/microbiology , Inflammation/metabolism , DNA, Bacterial/genetics , Mice, Inbred C57BL , Male , Female , Signal Transduction , Colitis/microbiology , Colitis/pathologyABSTRACT
BACKGROUND: Many researches have reported the impairment of regulatory T cells (Tregs) in autoimmune hepatitis (AIH), whilst the change of Tregs in peripheral blood remains controversial. We performed this systematic review and meta-analysis to clarify the numerical change of circulating Tregs in AIH patients compared with healthy individuals. METHODS: Relevant studies were identified from Medline, PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, and WanFang Data. Twenty-nine studies involving 968 AIH patients and 583 healthy controls were included. Subgroup analysis stratified by Treg definition or ethnicity was performed, and analysis of active-phase AIH was conducted. RESULTS: The proportions of Tregs among CD4 T cells and PBMCs were generally decreased in AIH patients compared with healthy controls. Subgroup analysis showed that circulating Tregs identified by CD4+CD25+/high, CD4+CD25+Foxp3+, CD4+CD25+/highCD127-/low, and Tregs in Asian population were decreased among CD4 T cells in AIH patients. No significant change of CD4+CD25+/highFoxp3+CD127-/low Tregs and Tregs in Caucasian population among CD4 T cells were found in AIH patients, whereas the number of studies was limited in these subgroups. Moreover, analysis of the active-phase AIH patients showed that Treg proportions were decreased generally, whereas no significant differences in Tregs/CD4 T cells were observed when markers CD4+CD25+Foxp3+, CD4+CD25+/highFoxp3+CD127-/low were used or in Caucasian population. CONCLUSIONS: The proportions of Tregs among CD4 T cells and PBMCs were decreased in AIH patients compared with healthy controls generally, whereas Treg definition markers, ethnicity, and disease activity had influence on the results. Further large-scale and rigorous study is warranted.
Subject(s)
Hepatitis, Autoimmune , T-Lymphocytes, Regulatory , Humans , CD4-Positive T-Lymphocytes , Interleukin-2 Receptor alpha Subunit , Ethnicity , Forkhead Transcription FactorsABSTRACT
Novel treatments for autoimmune hepatitis (AIH) are highly demanded due to the limitations of existing therapeutic agents. Costunolide is a promising candidate due to its anti-inflammatory and hepatoprotective function, but its effect in AIH remains obscure. In this study, we integrated network pharmacology and experimental validation to reveal the effect and mechanism of costunolide in AIH. A total of 73 common targets of costunolide and AIH were obtained from databases. Pathway enrichment analysis indicated that PI3K-AKT pathway was the core pathway of costunolide in AIH. Protein-protein interaction network analysis and molecular docking revealed that SRC and IGF1R might play critical roles. In two murine AIH models, costunolide significantly attenuated liver injury, inflammation, and fibrosis reflected by the liver gross appearance, serum transaminases, necrosis area, spleen index, immune cell infiltration, and collagen deposition. Western blot and immunohistochemistry confirmed that phosphorylated AKT, SRC, and IGF1R were upregulated in AIH models, and costunolide administration could inhibit the phosphorylation of these proteins. In summary, costunolide significantly ameliorates murine AIH. The therapeutic effect might work by suppressing the activation of PI3K-AKT pathway and inhibiting the phosphorylation of SRC and IGF1R. Our research reveals the potent therapeutic effect of costunolide in AIH and the potential role of SRC and IGF1R in AIH for the first time, which may further contribute to the novel drug development for AIH and other autoimmune diseases.
