LRCH1 suppresses migration of CD4⁺ T cells and refers to disease activity in ulcerative colitis

Abstract

Background: Ulcerative colitis (UC) is a chronically remittent and progressive inflammatory disorder. LRCH1 is reported to be involved in the immune-regulation of several diseases. However, the exact roles of LRCH1 in UC are still obscure. Materials and Methods: LRCH1 expression was analyzed in the inflamed mucosa and peripheral blood mononuclear cells (PBMCs) from patients with UC by quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4 + T cells were transfected with lentivirus-expressing LRCH1 (LV-LRCH1) or LV-sh-LRCH1, and cytokine expression was determined by using flow cytometry, quantitative RT-PCR and ELISA. Transfected CD4 + T cells were harvested to examine the capacity of chemotaxis using Transwell plate. Results: LRCH1 expression was highly decreased in colonic mucosa and PBMCs from patients with A-UC, and negatively correlated with disease activity. Up or down regulation of LRCH1 did not affect the differentiation of CD4 + T cells, and the related cytokines expression. Moreover, LRCH1 inhibited migratory capacity of CD4 + T cells toward CXCL12 by PKCα. Conclusion: LRCH1 plays an important role in the pathogenesis of UC, possibly through modulating the migration of CD4 + T cells. Therefore, targeting LRCH1 might serve as a novel therapeutic approach in the management of UC.

Structure and Emerging Functions of LRCH Proteins in Leukocyte Biology

“…Hence, LRCH1-deficient mice show improved clearance of infection with influenza and L. monocytogenes compared to WT mice and LRCH1-deficient cytotoxic T cells clear B16-MO5 tumor cells more efficiently than WT cells. A more direct regulation of the actin cytoskeleton by LRCH proteins is reported in CD4 + T cells (Xu et al, 2017;Wang et al, 2020). Here, LRCH1 has been identified as an inhibitory binding partner of DOCK8.…”

“…Strikingly, LRCH mRNA levels are regulated under inflammatory conditions. In the colonic mucosa of ulcerative colitis patients, LRCH1 expression is markedly decreased and disease severity more pronounced with lower levels of LRCH1 expression (Wang et al, 2020). In colorectal cancer, a potential complication of ulcerative colitis, expression of LRCH3 is increased compared to colorectal tissues of healthy individuals and expression of LRCH4 is increased in colorectal cancer patient samples with more advanced stages of cancer (Piepoli et al, 2012;Huo et al, 2017).…”

“…Accordingly, LRCH1-deficient CD4 + T cells present a more severe EAE phenotype due to increased Cdc42 activity and CD4 + T cell migration. Similarly, migration of CD4 + T cells from ulcerative colitis patients is increased compared to CD4 + T cells from healthy individuals ( Wang et al, 2020 ). Here, CD4 + T cells mediate the pathogenesis of ulcerative colitis and massively infiltrate into the colonic mucosa, potentially by a mechanism negatively regulated by LRCH1 as migration of CD4 + T cells from ulcerative colitis patients is reduced by LRCH1 overexpression.…”

Critical roles of RGS16 in the mucosal inflammation of ulcerative colitis

“…To test our hypothesis of whether RGS16 expression is associated with the disease activity in patients with ulcerative colitis, the disease severity of the patients was evaluated according to international standard criteria, such as the Mayo index. Slight ulcerative colitis was defined by a Mayo index of 3–5, mild ulcerative colitis by a Mayo index of 6–10 and severe ulcerative colitis by a Mayo index of 11–12 [ 28 ]. We performed Spearman’s correlation analysis and found a significant correlation between RGS16 expression in inflamed mucosa with the Mayo index and UCEIS in patients with ulcerative colitis (Fig.…”

Colorectal Cancer and Immunity: From the Wet Lab to Individuals

“…In contrast, a larger pore size allows cells to migrate through the membrane. For the study of human-derived immune cell migration, a 3 to 5 µm pore size membrane is usually sufficient [ 57 , 58 , 59 ]. In Transwell coculture, immune cells (PBMCs or isolated subpopulations of immune cells) are seeded onto the upper layer of the insert, while the tested molecules, CM, or attached cells are deposited in the lower chamber.…”