Innate lymphoid cells in the initiation, regulation and resolution of inflammation

Abstract

A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases.

Figure 1. Development and heterogeneity of the ILC family

ILCs develop from distinct progenitors in the fetal liver or bone marrow. All ILCs develop from common lymphoid progenitors (CLPs), which can differentiate into NK cell progenitors (NKp) or common helper innate lymphoid precursors (CHILPs). CHIPs can further differentiation to lymphoid tissue inducer (LTi) cells through α4β7 integrin-expressing intermediate populations, or to other ILC populations through differentiation to a PLZF-dependent ILC progenitor (ILCp). Further sequential engagement of transcription factors, cytokines and microbial signals is critical for the development of three distinct groups of mature ILCs. ILC1 express T-bet, are responsive to IL-12, and produce IFNγ. ILC2 highly express GATA3, are responsive to IL-25, IL-33 and TSLP, and produce IL-4, IL-5, IL-9, IL-13 and Areg. ILC3 express RORγt, are responsive to IL-1β and IL-23, and produce IL-17 and/or IL-22.

Figure 2. ILCs promote acute inflammation to mediate innate immunity to pathogens

ILCs promote innate immune responses to a number of pathogens in the intestine. (a) ILC1 promote innate immunity to intracellular pathogens, such as Toxoplasma gondii, by producing TNF and IFNγ in response to DC-derived IL-12 and subsequently promoting recruitment of inflammatory myeloid cells. (b) Following infection with the helminth parasites Nippostrongylus brasiliensis or Trichuris muris, ILC2 produce IL-13 in response to epithelial-cell derived-IL-25 and IL-33, which increases smooth muscle contractility and mucus production from goblet cells. (c) ILC3 produce IL-17 and IL-22 in response to DC-derived IL-23 and IL-1β, which promotes innate immunity to fungi and extracellular bacteria, such as Citrobacter rodentium and Candida albicans. IL-17 and IL-22 promote neutrophil recruitment to the intestine and the production of antimicrobial peptides from IECs.

Figure 3. ILC2 and ILC3 promote the resolution of inflammation and tissue repair

(a) Following viral infection in the lung, airway epithelial cells are damaged and produce IL-33 in conjunction with resident myeloid cell populations. ILC2 respond to IL-33 and produce amphiregulin, which promotes repair of the airway epithelium. (b) In lymphoid tissues, such as the spleen and thymus, stromal cell damage induced by viral infection or irradiation results in increased numbers of ILC3 and cytokine production, in part through production of DC-derived IL-23. ILC3 directly promote restoration of stromal cell compartments through production of LTα1β2 and IL-22, which increase the proliferation and survival of tissue resident stromal cells. (c) In the intestine, ILC3 responses can be limited by a regulatory loop whereby commensal bacteria induce IEC expression of IL-25, which acts on DCs to limit ILC3 cytokine responses in a contact-dependent manner. In contrast, upon chemical-, infection- or irradiation-induced damage of the intestine, ILC3 are activated by DC-derived IL-1β, IL-23, TL1A and retinoic acid (RA). Activation of ILC3 induces IL-22 production that directly promotes mucus production and epithelial cell repair, in part by acting directly on intestinal stem cells or progenitors.

Figure 4. ILCs can promote chronic inflammation

(a) In response to infection or allergens ILC2 responses are elicited in the lung (and skin) by epithelial cell- and myeloid cell-derived IL-25, IL-33 and TSLP. Further, ILC2 responses can be enhanced by basophil-derived IL-4 or mast cell-derived prostoglandin D2 (PGD2). Activated ILC2 can subsequently promote chronic inflammation via IL-5-dependent eosinophil recruitment, IL-13-mediated contraction of smooth muscle cells, collagen deposition, and alternatively activated macrophage (AAMac) differentiation, or MHCII-mediated enhancement of Th2 cell responses, resulting in allergy and fibrosis. (b) In patients with psoriasis and mouse models of skin inflammation, ILC3 responses are increased, which can occur in response to DC-derived IL-23. ILC3 largely promote skin inflammation through production of IL-22 and IL-17. Further, ILC3 are increased in the BAL of patients with asthma and in mouse models of obesity-induced asthma. In mice this occurs through activation of the NLRP3 inflammasome and macrophage production of IL-1β. IL-1β activates ILC3 to produce IL-17 and directly mediate airway inflammation. (c) In the intestine ILC3 can promote IL-22-dependent progression of tumors, which is in part dependent upon DC-derived IL-23. Further, ILC3 can mediate tissue inflammation in the intestine in response to DC-derived IL-23 and IL-12. This may occur through production of IL-17 by ILC3, production of IFNγ following loss of RORγt in ILC3 and differentiation to ex-ILC3, or direct activation of tissue resident ILC1.

Figure 5. ILCs can prevent or limit chronic inflammation

(a) In the intestine, ILC2 respond to epithelial cell-derived IL-33, IL-25 and vasoactive intestinal peptide (VIP) to promote IL-5 and IL-13-dependent recruitment of eosinophils and differentiation of alternatively activated macrophages (AAMacs). This process also occurs in the adipose tissues, however the sources of IL-25 or IL-33 are less well defined. Differentiation of AAMacs or direct stimulation of adipocytes with IL-13 or methionine-enkephalin peptides (met-enk) can promote metabolic homeostasis through a process known as beiging in the adipocytes. (b) ILC3 can limit chronic inflammation by regulating innate and adaptive immune responses in the intestine. ILC3 responses are induced in response to myeloid cell- and DC-derived IL-1β and IL-23 following recognition of pathogenic or commensal microbes. Production of ILC3-derived LTα1β2 or LTα3 can promote IgA production by B cells indirectly by modulating stromal cell or DC responses. Production of ILC3-derived GM-CSF can influence myeloid cell homeostasis to subsequently promote regulatory T cell (Treg) responses to food antigens. ILC3-intrisic MHCII can directly kill commensal bacteria-specific CD4 T cells with the potential to cause intestinal inflammation. Production of IL-22 by ILC3 can promote antimicrobial peptides by IECs to limit colonization with commensal bacteria, such as segmented filamentus bacteria (SFB), or regulate the anatomical localization of lymphoid tissue resident commensal bacteria. Further, ILC3-derived IL-22 can induce fucosylation of IECs to promote colonization with beneficial bacteria.