Immune system of the skin and ILCs
The skin acts as an interface between host and environment, and serves as a mechanical and biological barrier against chemical and physical effects and pathogenic microorganisms. Skin-associated immune cells are important for this protection: macrophages, DCs, mast cells, T cells, B cells, neutrophils and recently described ILCs orchestrate the defense while taking part in homeostatic functions.43, 44Studies in humans revealed that during homeostatic skin conditions, ILCs are mainly localized in the dermis, with the exception of ILC3s which are found within the epidermis.45, 46 A recent study reported that ILCs are compartmentalized within sebaceuous glands, and a subset of RORγt+ ILCs found within hair follicles can modulate these sebaceous glands.47 ILC2s are the most abundant subset of ILCs found in the healthy skin, constituting nearly one third of the skin-resident lymphocytes in mice.45ILC3s in healthy human skin are also present in high numbers.48 Skin ILCs migrate to the tissue from the circulation. This idea is supported by the expression of CCR10 and cutaneous leukocyte antigens in some of the circulating ILCs.36, 49
In the steady state, ILC2s are involved in homeostasis and wound healing.44 Multiphoton microscopy study reveals the perivascular distribution of ILC2s and their close proximity to skin resident mast cells, suggesting that these cells affect each other during homeostasis and inflammation.45 ILC2s are the main source of IL-13 in the skin resulting in the inhibition of the mast cell functions.45 ILC2s express amphiregulin (AREG) which is an epidermal growth factor related molecule and plays an important role in tissue repair in the skin and airways after acute epithelial damage.50,51 Recently, it was shown that acute cutaneous injury promoted ILC2 response which prevented epithelialization and effective wound closure.52 ILC3s have also been shown to take part in skin repair. Both mouse and human studies showing accumulation of IL-17F-producing ILC3s in the wound site. In an ILC3-deficient mouse model, a delay in epidermal proliferation, macrophage accumulation and wound healing was observed, demonstrating ILC3 contribution in the repair of skin tissue.53
In addition to homeostasis and wound repair, ILCs have an important role in disease processes of the skin. Exposure of the skin to allergens and exogenous molecules frequently trigger type 2 cytokine production associated with elevated TSLP, IL-33 and IL-25.45, 51, 54-56 This is characterized by the secretion of IL-4, IL-5 and IL-13 by ILC2s, increased eosinophil numbers and mast cell activation.45, 51, 56 ILC2s can also disrupt keratinocyte tight junction barrier integrity by their IL-13 production.57 ILC2 receptors for IL-25, IL-33 and TSLP is upregulated in AD skin lesions 36, 51, 58, 59 and an increase in the proportion of ILC2s is also observed, suggesting an important role of ILC2s in skin inflammation.45Additionally, a novel mechanism for the ILC2 activation in AD is the tumor-associated surface molecule B7-H7 which increases in AD skin and activates NKp30 expression on ILC2s in human.60Experimental models have demonstrated that ILC2s and their stimulator epithelial cytokines TSLP, IL-13 and IL-25 play an important role in the pathogenesis of food allergy.7, 61 Recently, a study involving murine model reported that ILC2 is an essential mediator of skin to gut crosstalk following mechanical skin injury. ILC2 was driven by IL-25 and IL-33 and resulted in the expansion of intestinal mast cells, thereby promoting IgE-mediated food anaphylaxis.62 Therefore, ILC2s may be an important and potent driver of the skin immune system in type 2 inflammation like food allergy and AD (Figure 2).