IL‐13 in dermal type‐2 dendritic cell specialization: From function to therapeutic targeting

Abstract

Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.

The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis

“…Atopic dermatitis is a disease related to type 2 immunity activation in response to environmental stimuli (2). Both adaptive and innate immune systems are involved in Type 2 immunity (2,12). Indeed, in the innate immune system activation, it has been showed that key roles are played by Group 2 lymphoid cells (ILC2), mast cells, basophils, eosinophils, and macrophages activated by interleukin (IL)-4 and/or IL-13 (12)(13)(14)(15).…”

“…Both adaptive and innate immune systems are involved in Type 2 immunity (2,12). Indeed, in the innate immune system activation, it has been showed that key roles are played by Group 2 lymphoid cells (ILC2), mast cells, basophils, eosinophils, and macrophages activated by interleukin (IL)-4 and/or IL-13 (12)(13)(14)(15). Furthermore, also keratinocyte is implicated in this mechanism by expressing an increased level of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) (12)(13)(14)(15).…”

“…Indeed, in the innate immune system activation, it has been showed that key roles are played by Group 2 lymphoid cells (ILC2), mast cells, basophils, eosinophils, and macrophages activated by interleukin (IL)-4 and/or IL-13 (12)(13)(14)(15). Furthermore, also keratinocyte is implicated in this mechanism by expressing an increased level of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) (12)(13)(14)(15). These cytokines may act as alarmins, inducing the production of IL-4, IL-13, and IL-5 from both T helper (Th)2, and ILC2 cells, which in turn trigger the complex inflammatory cascade that underlies the clinical expression of AD (16).…”

“…Additionally, adaptive immune responses of T and B cells, including CD4 Th2 cells and Th17 cytokines, are required for the development and progression to systemic inflammation in the atopic march (16). The activation of Th2 and ILC2 pathways are at the center of type 2 inflammation (12)(13)(14)(15). Conversely, although the expression of Th17-cytokines such as IL-17A has consistently been found to be increased in AD lesions, the role of these cytokines in AD pathogenesis is controversial (16).…”

“…Indeed, the follicular Th cells of the lymph node, regulating B-cell immunity, invariant natural killer T2 cells, and basophils express IL-4, while mucosal ILC2s mostly express IL-13 and little IL-4 (17). This difference suggests that IL-13 and IL-4 may have distinct actions in Th2 immunity (12). Indeed, it has been showed that IL-4, which drives the T cell differentiation, may have a role in the first steps of the pathogenesis of AD, while IL-13 effects appear to influence the peripheral tissue cells and the effector phase of the immune response (12)(13)(14)(15)(16)(17).…”