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).