Circadian clock component PER2 negatively regulates CD4 T cell IFN-γ production in ulcerative colitis. Mucosal immunology Period circadian clock 2 (PER2) is involved in the pathogenesis of various inflammatory and autoimmune diseases. However, there are gaps in our understanding of the role of PER2 in regulating CD4 T cells beyond its time-keeping function in ulcerative colitis (UC) pathogenesis. Our findings revealed PER2 was predominantly expressed in CD4 T cells, while it was significantly decreased in the inflamed mucosa and peripheral blood CD4 T cells of UC patients compared with that in Crohn's disease (CD) patients and healthy controls (HC). Notably, PER2 expression was significantly recovered in UC patients in remission (R-UC) compared to that in active UC patients (A-UC) but not in CD patients. It was negatively correlated with the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Crohn's Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn's disease (SES-CD), and C-reactive protein (CRP), respectively. Overexpression of PER2 markedly inhibited IFN-γ production in UC CD4 T cells. RNA-seq analysis showed that overexpression of PER2 could repress the expression of a disintegrin and metalloproteinase 12 (ADAM12), a costimulatory molecule that determines Th1 cell fate. Mechanistically, cleavage under targets and tagmentation (CUT&Tag) analysis revealed that PER2 down-regulated ADAM12 expression by reducing its binding activity, thereby suppressing IFN-γ production in UC CD4 T cells. Additionally, our data further demonstrated that ADAM12 was upregulated in CD4 T cells and inflamed mucosa of A-UC patients compared to HC. Our study reveals a critical role of PER2 in regulating CD4 T cell differentiation and highlights its potential as a therapeutic target for UC treatment. 10.1016/j.mucimm.2024.07.010

IL-12 and Mucosal CD14+ Monocyte-Like Cells Induce IL-8 in Colonic Memory CD4+ T Cells of Patients With Ulcerative Colitis but not Crohn's Disease. Chapuy Laurence,Bsat Marwa,Rubio Manuel,Sarkizova Sisi,Therrien Amélie,Bouin Mickael,Orlicka Katarzina,Weber Audrey,Soucy Geneviève,Villani Alexandra-Chloé,Sarfati Marika Journal of Crohn's & colitis BACKGROUND AND AIMS:CD14+ mononuclear phagocytes [MNPs] and T cells infiltrate colon in ulcerative colitis [UC]. Here we investigated how CD14+ MNPs and the cytokines they produce shape the colonic effector T cell profile. METHODS:Colonic or mesenteric lymph node [mLNs] CD4+ T cells isolated from UC or Crohn's disease [CD] patients were stimulated with cytokines or autologous CD14+ MNPs. Cytokine expression was assessed by intracytoplasmic staining and multiplex ELISA. Unsupervised phenotypic multicolour analysis of colonic CD14+ MNPs was performed using the FlowSOM algorithm. RESULTS:Among CD14+CD64+HLA-DR+SIRPα + MNPs, only the pro-inflammatory cytokine-producing CD163- subpopulation accumulated in inflamed UC colon and promoted mucosal IL-1β-dependent Th17, Th17/Th1, Th17/Th22 but not Th1 responses. Unsupervised phenotypic analysis of CD14+CD64+ MNPs segregated CD163- monocyte-like cells and CD163+ macrophages. Unexpectedly, IL-12, IL-1β and CD163-, but not CD163+, cells induced IL-8 expression in colonic CD4+ T cells, which co-expressed IFN-γ and/or IL-17 in UC and not CD. The CD163- monocyte-like cells increased the frequency of IL-8+IL-17+/-IFN-γ +/- T cells through IL-1β and IL-12. Finally, colonic IL-8+ T cells co-expressing GM-CSF, TNF-α and IL-6 were detected ex vivo and, promoted by IL-12 in the mucosa and mLNs in UC only. CONCLUSIONS:Our findings established a link between monocyte-like CD163- MNPs, IL-12, IL-1β and the detection of colonic memory IL-8-producing CD4+ T cells, which might all contribute to the pathogenesis of UC. 10.1093/ecco-jcc/jjz115

Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. Kamada Nobuhiko,Hisamatsu Tadakazu,Okamoto Susumu,Chinen Hiroshi,Kobayashi Taku,Sato Toshiro,Sakuraba Atsushi,Kitazume Mina T,Sugita Akira,Koganei Kazutaka,Akagawa Kiyoko S,Hibi Toshifumi The Journal of clinical investigation Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD. 10.1172/JCI34610

Eicosapentaenoic acid mitigates ulcerative colitis-induced by acetic acid through modulation of NF-κB and TGF-β/ EGFR signaling pathways. Life sciences BACKGROUND:Ulcerative colitis (UC) is a chronic mucosal inflammation of the large intestine that mostly affects the rectum and colon. The absence of safe and effective therapeutic agents encourages the discovery of novel therapeutic agents to effectively treat UC and its complications. The purpose of this research was to examine the protective impact of Eicosapentaenoic acid (EPA) in rats with UC induced by acetic acid (AA). METHOD:AA (2 ml, 3 % v/v) was injected intrarectally to cause UC. Before administering AA, EPA (300 and 1000 mg/kg) was given orally for 28 days. RESULTS:EPA inhibited AA-induced UC by enhancing colonic histopathological changes like inflammation, goblet cell loss, glandular hyperplasia and mucosal ulceration, concomitant with a reduction in colon weight, colon weight/length ratio, C-reactive protein (CRP), and serum lactate dehydrogenase (LDH). EPA also effectively restored the imbalance between oxidants and antioxidants caused by AA. In addition, EPA increased the levels of trefoil factor-3 (TFF-3) and glucagon-like peptide-1 (GLP-1), while significantly reducing the expression of nuclear factor kappa B (NF-κB), interferon-γ (IFN-γ), and interleukin-6 (IL-6), transforming growth factor-1(TGF-β1), and phosphorylated epidermal growth factor receptor (P-EGFR), phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) expression in colonic tissues. CONCLUSION:EPA inhibited AA-induced UC in rats by modulating the TGF-β/P-EGFR and NF-κB inflammatory pathways, regulating the oxidant/antioxidant balance, and enhancing the colon barrier integrity. 10.1016/j.lfs.2023.121820