Innate lymphoid cells in tissue homeostasis and diseases

Abstract

Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver.

Keywords: Homeostasis; Inflammatory diseases; Innate lymphoid cells; Intestine; Liver.

Figure 1

Innate lymphoid cell family. Each individual ILC subset is characterized by differential expression of transcription factors and patterns of expression of cytokines. ILCs can be activated by a diverse array of cytokines and can contribute to immunity, inflammation and maintenance of tissue homeostasis. IL: Interleukin; IFN-γ: Interferon γ; ILC: Innate lymphoid cell.

Figure 2

Innate lymphoid cell family plays different roles in the liver. ILCs can develop different functions depending on the organ and environment in which they are found. In the liver (A) IL-33, produced by hepatic cells, can act on ILC2s, promoting the release of anti-inflammatory cytokines, such as IL-13 and IL-4. These cytokines can activate HSCs, via STAT4, promoting tissue remodeling and fibrosis. On the other hand, IL-22, produced by ILC3s, acts on HSCs, via STAT3, SOCS3 and p53, promoting their senescence and ameliorating liver fibrosis; B: IL-17 can be released by the intrahepatic subpopulation ILC3s, during the virus infection promoting the clearance of the virus; C: IL-22 can be produced by ILC1s and cNK cells in the liver, contributing to liver regeneration via ATP-P2X1. Therefore, different cytokines can be manipulated, as therapeutic targets, in benefit of hepatic inflammation, fibrosis and tissue regeneration. IL: Interleukin; IFN-γ: Interferon γ; ILC: Innate lymphoid cell; HSCs: Hepatic stellate cells.