Gpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells

Abstract

BackgroundDysfunction of the immune system would disturb the intestinal homeostasis and lead to inflammatory bowel disease (IBD). Dendritic cells (DCs) help maintain intestinal homeostasis and immediately respond to pathogens or injuries once the mucosa barriers are destroyed during IBD. G protein-coupled receptors(GPR)174 is an essential regulator of immunity that is widely expressed in most immune cells, including DCs. However, the role of GPR174 in regulating the immune function of DC in colitis has not been investigated.MethodsDextran sodium sulfate (DSS) was administered to establish the mice colitis model. Data of weight, length of colon, disease activity index (DAI), and macroscopic scores were collected. The flow cytometry was used to detect the infiltrations of T cells and DCs, the mean fluorescence intensity (MFI) of CD80, CD86, CD40, and major histocompatibility complex-II (MHC-II). And T cells proliferataion was measured by carboxyfluorescein diacetate succinimidyl ester (CFSE). The expression of cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), interleukin -4 (IL-4)) and GPR174 mRNA were measured by Elisa, quantitative polymerase chain reaction (qPCR), and immunofluorescence. RNA of bone-marrow-derived dendritic cells (BMDCs) was extracted for sequencing. Adoptive transfer of BMDCs was administrated intravenously.ResultsGpr174-/- mice exposed to 3% DSS showed significant alleviation characterized by reduced loss of weight, more minor colon damage, and better DAI and macroscopic scores. The expression of pro-inflammatory cytokines (TNF-α, IL-6) decreased, while anti-inflammatory cytokine (IL-10) increased compared with WT mice. In vitro, Gpr174-/- BMDCs showed less maturity, with a declined expression of MHC-II, CD80, CD86 and reduced TNF-α, higher IL-10 after LPS stimulation. Gpr174-/- BMDCs were less capable of activating OT-II naïve CD4+ T cells than WT BMDCs and induced more Th0 cells to differentiate into Treg while less into Th1. Furthermore, the transcriptome sequencing analysis exhibited that Gpr174 participated in TNF-α (NF-κB) signaling, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways. Adoptive transfer of Gpr174-/- BMDCs to WT mice ameliorated DSS-induced colitis.ConclusionOur study indicated that GPR174 was involved in the pathogenesis of IBD by regulating the maturation of the dendritic cells to maintain immune homeostasis. TNF-α (NF-κB) signaling pathway, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways may be the target pathway.

Oxidative Stress, Inflammation, Gut Dysbiosis: What Can Polyphenols Do in Inflammatory Bowel Disease?

“…These excessive ROS can act as upstream stimuli to evoke aberrant activation of the intestinal immune system, causing damage to the intestinal mucosal barrier, including a decrease in mucous secretion, antimicrobial peptide secretion, and the destruction of tight junctions [ 15 ]. Importantly, radical immune cells activate inflammatory signaling pathways such as NF-κB, JAK/STAT, and MAPK signaling pathways [ 16 , 17 , 18 ], promote the release of proinflammatory factors (e.g., TNF-α, IL-6, and IL-1β) and oxidases (e.g., iNOS, COX-2, and NOX [ 19 , 20 ]), and further increase the level of oxidative stress in the intestinal tract [ 21 ], which will remold the gut microbiota and form a loop of oxidative stress–ROS–inflammation–ROS–oxidative stress ( Figure 1 ). Accordingly, such a loop can be used as a potential therapeutic target to avoid the occurrence and progression of intestinal inflammation by alleviating oxidative stress in the intestine and reducing the stimulation of gut microbiota and immune cells by ROS, thereby recovering the intestinal mucosal barrier.…”

IGSF6 is a biomarker associated with anti-tumor immune response in lung adenocarcinoma

“…The GSEA enrichment analysis showed that gene sets grouped according to IGSF6 expression were mainly enriched in cytokine-receptor interaction and intercellular interaction. It has been well established that antigen peptide-MHCII complex presented by macrophages and DCs is essential for the activation of Th1 cells [27][28][29][30]. Previous studies have also proposed that IGSF6 may be closely related to antigen uptake, or the recirculation of DCs [13].…”

Schisandrin A Suppresses Inflammation in DSS-induced IBD Mice and H2O2-induced MODE-K Cells through Wnt/β-Catenin Signaling

“…MC group mice continuously drank 3% DSS solution for 16 days based on the method described previously with minor modifications (Wang et al, 2020; Wei et al, 2022; Zhou et al, 2022). Except for mice in the NC group that were provided pure water by gavage, the SASP and SchA groups were administered their respective drugs daily.…”