TLR5 Signaling in the Regulation of Intestinal Mucosal Immunity

Abstract

Toll-like receptor 5 (TLR5) is a pattern recognition receptor that specifically recognizes flagellin and consequently plays a crucial role in the control of intestinal homeostasis by activating innate and adaptive immune responses. TLR5 overexpression, on the other hand, might disrupt the intestinal mucosal barrier, which serves as the first line of defense against harmful microbes. The intestine symbiotic bacteria, mucous layer, intestinal epithelial cells (IECs), adherens junctions (such as tight junctions and peripheral membrane proteins), the intestinal mucosal immune system, and cytokines make up the intestinal mucosal barrier. Impaired barrier function has been linked to intestinal illnesses such as inflammatory bowel disease (IBD). IBD is a persistent non-specific inflammatory illness of the digestive system with an unknown cause. It is now thought to be linked to infection, environment, genes, immune system, and the gut microbiota. The significance of immunological dysfunction in IBD has received more attention in recent years. The purpose of this paper is to explore TLR5's position in the intestinal mucosal barrier and its relevance to IBD.

Keywords: inflammatory bowel disease; intestinal immune; intestinal mucosal barrier; microbes; toll-like receptor 5.

Figure 1

The various roles of different kinds of intestinal epithelial cells (IECs) and the crosstalk between IECs and LPDCs. IECs can secret various components to form a mucus layer and chemical barrier to resist the invasion of pathogenic microorganisms in the gut. LPDCs can obtain antigens by interacting with IECs in four ways: (a) trans-epithelial dendrites (Teds) from dendritic cells (DCs). (b) goblet cell-associated antigen passages (GAPs) from goblet cells. (c) auto-antigens from apoptotic epithelial cells. (d) antigens acquired by M cells. (Created with BioRender.com).

Figure 2

The flagellin-dependent TLR5 signaling pathway. The flagellin activates the TLR5 after the damage of the intestinal mucosal barrier. The activated TLR5 recruits intracellular adaptor protein MyD88 to form a complex with IRAK 4 and IRAK1/2 kinase called Myddosome and then activates TAK1. After being sensitized, TAK1 activates the MAPK pathway and the IKK complex composed of catalytic subunits IKKα, IKKβ, and regulatory subunit NEMO (also known as IKKγ). IKK complex phosphorylates NF-κB inhibitory protein IκBα and leads to proteasome degradation so that NF-κB can translocate into the nucleus to induce pro-inflammatory gene expression. Then the NF-κB and AP-1 translocate into the nucleus, promoting the transcription of pro-inflammatory cytokines genes. (Created with BioRender.com).

Figure 3

Response to flagellin. (a) Under steady-state flagellin delivery through the IECs to the immature DCs, and LPDC presents flagellin in a tolerant manner, which catalyzes the conversion of vitamin A metabolite retinaldehyde to retinoic acid and secretion of IL-33 by expressing high levels of aldehyde dehydrogenase, thereby inducing immature CD4+T cells to differentiate into Foxp3+Treg. (b) Flagellin-stimulated endothelial cells rapidly induce proinflammatory mediators through the TLR5-related signal pathway and therefore attract LPDCs. After activation, LPDCs migrate into lymphatic vessels and induce the differentiation of naive B cells into plasma cells that produce IgA, IL-17, and IL-22, and positively regulate the differentiation of Th17-producing cells, while the involvement of TLR5 limits the production of Treg cells. Also, LPDCs can rapidly produce IL-23 through the flagellin-TLR5 signal pathway, thereby stimulating group 3 innate lymphoid cells (ILC3) to produce IL-22, promoting IECs recovery and inducing RegIIIγ expression. (Created with BioRender.com).