Deciphering the Role of Innate Lymphoid Cells Group 3 in the Gut Microenvironment: A Narrative Review of Their Novel Contributions to Autoimmune Disease Pathogenesis

Abstract

Type 3 Innate lymphoid cells (ILC3s) play a crucial role in intestinal immune function by serving as an innate effector that contributes to early-life defense against pathogens and helps protect the intestines from bacterial infections. ILC3s exert their immune function through cytokine secretion, patrolling actions and the generation of memory ILC3s that aid in repairing epithelial tissue and preserving mucosal barrier integrity. Moreover, dysregulation of ILC3s function has been implicated in the pathogenesis and progression of autoimmune diseases. This comprehensive review aims to explore the interactions between gut microbes, gut microbial metabolites, and diet in relation to ILC3s within the context of the gut microenvironment. Furthermore, the gut microenvironment has the potential to influence distant extra-intestinal sites through immunomodulation, thereby modifying their risk of inflammation. The gut has emerged as a significant focus of autoimmune disease research in recent years. However, the relationship between gut ILC3s and autoimmune diseases remains poorly understood. This paper aims to examine the potential association between ILC3s and autoimmune diseases.

Keywords: IL-22; ILC3s; ankylosing spondylitis; rheumatoid arthritis; short-chain fatty acids; systemic lupus erythematosus.

Figure 1

AhR is highly expressed in ILC3s and is required for ILC3s development and maintenance. The gut microbiota-derived tryptophan metabolites indole and indole-3-acetic acid bind to AhR to activate ILC3s and regulate IL-22 production. AhR ligand binds to AhR and enhances ILC3s to secrete IL-22 and prevent intestinal epithelial cell transformation through the DNA damage response (DDR). In ILC3s, WASH recruits Arid1a to the AhR promoter, thereby activating AhR expression.

Figure 2

Retinoic acid regulates ILC3s homing and promotes ILC3s growth. Retinoic acid induces a homing receptor switch that allows ILC3s and ILC1s to migrate to the intestine, but ILC2s migration to the intestine is not regulated by retinoic acid. Retinoic acid inhibits ILC2s but increases ILC3s numbers and IL-22 expression, mainly by promoting IL-22 production in IL-1β- and IL-23-stimulated ILC3s and by controlling LTi upstream of the transcription factor RORγt.

Figure 3

SCFAs are essential for the proliferation and effector function (IL-22 production) of colonic ILC3s to promote intestinal immunity. Gut microbiota ferment dietary fibre to produce SCFAs, which stimulate IL-22 production by ILC3s, mainly through activation of the AKT and STAT3 pathways. SCFAs, including acetate and butyrate, etc. Acetate activates FFAR2 to increase the production of IL-1β, which in turn increases ILC3s susceptibility to IL-1β, promotes IL-22 production, and also reduces ILC3s-induced IL-17A levels.

Figure 4

SFB in ILC3s function or homeostasis. SFB colonise epithelial cells and initiate an IL-22-mediated Stat3 signalling cascade leading to local SAA1/2 expression and can also maintain the epithelial cell barrier function in the ileum by promoting the phosphorylation of STAT3 (pSTAT3) in the intestinal epithelium, inducing the production of REG3γ and contributing to IL-22 production by ILC3s. At the same time, ILC3s express high levels of Sca-1 on its surface in response to SFB colonisation, high levels of Sca-1 in response to SFB colonisation. Diet is also closely related to SFB function, as carbohydrates or insoluble cellulose fibre can affect IL-22 production by ILC3s and STAT3 phosphorylation in the ileum.

Figure 5

Probiotic Akkermansia muciniphila maintains intestinal barrier stability. Akkermansia muciniphila promotes the production of SCFA propionate and acetate, and upregulates gene expression of antimicrobial peptides (eg Reg3a, Reg3b and Reg3g). Co-colonisation with another bacterium, Salmonella typhimurium, exacerbated the reduction in cuprocytes, but co-colonisation with P. distasonis led to an increase in IL-17-ILC3s, reinforcing the interactions between gut microbes and their contribution to the protective immune response.