Innate Lymphoid Cells: A Link between the Nervous System and Microbiota in Intestinal Networks

Abstract

Innate lymphoid cells (ILCs) are a novel family of innate immune cells that act as key coordinators of intestinal mucosal surface immune defense and are essential for maintaining intestinal homeostasis and barrier integrity by responding to locally produced effector cytokines or direct recognition of exogenous or endogenous danger patterns. ILCs are also involved in the pathogenesis of inflammatory bowel disease (IBD). Many studies have demonstrated the occurrence of crosstalk between ILCs and intestinal microbiota, and ILCs have recently been shown to be connected to the enteric nervous system (ENS). Thus, ILCs may act as a key link between the nervous system and microbiota in intestinal networks. In this review, we briefly summarize the role of the ILCs in the intestinal tract (particularly in the context of IBD) and discuss the relationship between ILCs and the microbiota/ENS.

Figure 1

The main mechanisms regulating ILCs in IBD. The schematic shows the three ILC subgroup transcription factors and their secretory cytokines, which play proinflammatory (+) or anti- inflammatory (-) roles in IBD, and inhibiting “arrow” means suppression effects on ILCs. Particularly for ILC3s, macrophages secrete IL-1β, which induces RORγt⁺ ILC3s to produce colony stimulating factor 2 (CSF2) (shown by purple arrow). CSF2 then acts on dendritic cells (DCs) and macrophages to promote the secretion of regulatory factors and induce the transformation of immature T cells into mature regulatory T cells (Tregs), which are essential for inhibiting inflammation and maintaining intestinal homeostasis. Natural cytotoxicity receptor⁻ (NCR⁻) ILC3s express high levels of major histocompatibility complex (MHC) II, which is involved in processing and presenting antigens and can limit the response between CD4⁺ T cells and intestinal commensal bacteria, thereby inhibiting inflammation mediated by CD4⁺ T cells to prevent IBD. ILCregs can protect against innate intestinal inflammation by secreting IL-10 to suppress the activation of ILC1s, ILC3s, and autocrine TGF-β1 for the expansion and survival of ILCregs during intestinal inflammation. Furthermore, ILCs could mutually transform via induction by specific cytokines (shown by red font).

Figure 2

The main relationships between ILCs and the gut microbiota and between ILCs and the ENS in IBD. The gut microbiota can stimulate macrophagocytes to secrete IL-β, which can induce RORγt⁺ ILCs to produce IL-22. This process is also observed for IL-7, which is secreted by intestinal epithelial cells (IECs). IL-25, which is produced by IECs and stimulated by the gut microbiota, decreases the production of IL-22 by ILC3s. IL-22 can also induce fucosylation, which is required for host protection against enteric pathogens, in IECs. Microbial sensing and production of IL-1β by intestinal macrophages drive CSF2 secretion by ILC3s. Toll-like receptor 2 (TLR2) expressed on the surface of ILC3s can identify bacterial signals. ILC3 subsets express the neuroregulatory receptor tyrosine kinase (RET), which is activated by glial-derived neurotrophic factor family ligands (GFL) derived from enteric glial cells (EGCs), in response to IL-22 secretion. Neuronal messenger neuromedin U (NMU), produced by neurons, binds to NMUR1 on ILC2s, and ILC2s are activated to secrete innate type 2 cytokines. Activation of ILCs via the ENS or induction of cytokines via the gut microbiota can modulate the development or progression of IBD, as detailed in Figure 1. The gut microbiota is also associated with the ENS. Cytokines regulated by gut microbiota could modulate ENS activity directly or indirectly, e.g., IL-1β, which has its receptors on ENS neurons.