Communication between Mast Cells and Group 2 Innate Lymphoid Cells in the Skin

Abstract

The skin is a dynamic organ with a complex immune network critical for maintaining balance and defending against various pathogens. Different types of cells in the skin, such as mast cells (MCs) and group 2 innate lymphoid cells (ILC2s), contribute to immune regulation and play essential roles in the early immune response to various triggers, including allergens. It is beneficial to dissect cell-to-cell interactions in the skin to elucidate the mechanisms underlying skin immunity. The current manuscript concentrates explicitly on the communication pathways between MCs and ILC2s in the skin, highlighting their ability to regulate immune responses, inflammation, and tissue repair. Furthermore, it discusses how the interactions between MCs and ILC2s play a crucial role in various skin conditions, such as autoimmune diseases, dermatological disorders, and allergic reactions. Understanding the complex interactions between MCs and ILC2s in different skin conditions is crucial to developing targeted treatments for related disorders. The discovery of shared pathways could pave the way for novel therapeutic interventions to restore immunological balance in diseased skin tissues.

Keywords: ILC2s; MCs; disease; skin.

Figure 1

Mast cell (MC)-derived IL-4/IL-13 decreases E-cadherin expression in keratinocytes and subsequently attenuates E-cadherin-mediated suppression of IL-5 and IL-13 production from innate lymphoid cell type 2 (ILC2s). IL-33- and IL-25-stimulated ILC2s release IL13, a negative regulator for IgE-mediated responses in MCs. ILC2s-released IL-5 promotes the recruitment of eosinophils, which produce major basic protein (MBP) and eosinophil peroxidase (EPO) and, subsequently, stimulate MRGPRX2 (Mas-related G protein-coupled receptor member X2) on MCs. MC-released IL-5, maintaining the population of IL-10-expressing regulatory B cells, suppresses the activation of IL-13-producing ILC2s. ILC2s release IL-9, enhance the activation of Th9 cells, and, along with Th9-expressed IL-9, activate MCs to release IL-2, promoting ILC2 to produce more IL-9, resulting in a positive loop.

Figure 2

Skin mast cells (MCs) carrying the D816V+ mutation produce inflammatory mediators like IL-1β, TGF-β, PGD2, chymase, and tryptase proteases. This constant secretion activates ILC2s within the skin, creating a favorable environment that attracts circulating ILC2s through the CCR10 pathway. As a result, the persistent activation of ILC2s leads to the production of IL-9. This not only amplifies MC activity and skin symptoms but also facilitates the trafficking of ILC2s into the bloodstream.

Figure 3

ILC2s are more abundant in the lesions of individuals with atopic dermatitis. ILC2s exhibit increased expression of ST2, IL-17RB, and TSLP-R. They produce IL-13, IL-5, and IL-4 in response to signals from keratinocytes such as IL-33, IL-25, and TSLP, as well as PGD2 expressed by MCs. IL-5 activates eosinophils and MCs, while IL-13 suppresses MCs.

Figure 4

The expression of IL-9 in Th9 cells and IL-9 receptor in MCs results in the expansion of ILC2s in SSc patients with inflamed skin.

Figure 5

Inflammatory responses in patients with chronic spontaneous urticaria (CSU). Upregulation of IL-25, IL-33, and TSLP in keratinocytes contributes to the expansion of local ILC2s. The activated ILC2s then increase the expression of IL-13, which has a role in regulating MCs. In turn, MCs prolong the longevity of ILC2s and help to maintain cytokine secretion by their inflammatory mediators.