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.

Innate Lymphoid Cells: Regulators of Gut Barrier Function and Immune Homeostasis

“…ILC1s are regulated by Tbet and can produce IFN-γ, GM-CSF, granzyme, and perforin in response to IL-12, IL-18, or other activators such as pathogens or tumors. They cooperate with Th1 cells against intracellular microbes such as viruses, bacteria, or parasites [71,73,76,77]. Group 2 ILCs (ILC2s), similarly to Th2, express Gata3 and can produce IL-4, IL-5, IL-13, IL-9, and amphiregulin in response to IL-25, IL-33, and TSLP (thymic stromal lymphopoietin).…”

Innate Lymphoid Cells in Crohn’s Disease

“…The gut microbiota interacts with some cells (such as T cells and IECs) to induce or inhibit ILCs to secrete inflammatory cytokines. Additionally, the release of these cytokines can also change the intestinal flora ( 12 ). ILCs may link the intestinal flora and ENS and work together in the intestine ( 116 , 117 ).…”

“…Microbiota is closely related to ILC development. ILCs and the gut microbiata communicate with each other in an indirect manner via cytokine signaling, and these signals also combine with signals from intestinal epithelial cells (IECs) and macrophages ( 12 ). The commensal flora of the gut and the skin is known to directly influence the development of certain lymphocyte populations ( 13 – 15 ).…”

“…ILCs react to the gut microbiota by changing their structure, having protective or destructive effects on gut immunity. Among ILCs, the most important with regard to the gut microbiota are type 3 ILCs ( 12 ). The studies reported that intestinal type 3 ILC frequencies were severely reduced in mice lacking a commensal flora and frequencies increased with age in newborn mice with a few NKp46 + type 3 ILC in the intestine and thus correlating with commensal colonization ( 18 – 20 ).…”

“…Novel studies reported that when nerve cells receive an alert from the gut, specific instructions are passed on to ILCs to produce effectors that can repair intestinal damage. The process that protects the intestinal from inflammation and microbial infection via interactions between enteric glial cells (EGCs) (essential components of the ENS) and type 3 ILCs through neurotrophic factor signals ( 12 , 24 ). IL-22 secretion is up-regulated by activated enteric type 3 ILC via ECGs or/and directly regulated in the downstream of STAT3 activation by neurotrophic factors ( 24 ).…”