Role of Toll-like receptor 2 signaling in ultraviolet-induced inflammation

Abstract

Toll-like receptor (TLR) plays a crucial role linking innate and adaptive immune responses. In response to various exogenous and endogenous stimuli, TLR signaling elicits complex but tightly regulated immune response to protect the host and maintain tissue integrity. Ultraviolet light (UV) irradiation on skin causes acute inflammatory responses as well as the development of chronic photodamage and skin cancers, and triggers various immune responses. However, the role of TLR2 signaling in UV-induced inflammation has not been elucidated so far. A single dose of UV irradiation induced the transient up-regulation of TLR2 in mouse and human skin in vivo, as well as in human epidermal cell line HaCaT in vitro. Moreover, UV-induced TLR2 interacted with its adapter protein myeloid differentiation primary-response protein 88 (MyD88) or phosphoinositide 3-kinase (PI3K) in vivo. Mice with deficient TLR2 (TLR2 KO) showed enhanced UV-induced inflammatory responses, compared with wild-type (WT) counterparts. TLR2 KO mice showed significantly increased epidermal and dermal thickness as well as skin fold thickness, accompanied by an increase of Ki-67 (+) proliferative cells, compared with WT mice. The production of matrix metalloproteinase (MMP)13, proinflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α, and CXCL1, and UV-induced apoptosis was significantly augmented in TLR2 KO mice. Moreover, primary keratinocytes isolated from TLR2 KO mice were more susceptible to UV-induced apoptosis. Of particular interest, UV-irradiated TLR2 KO mice showed significantly less production of anti-inflammatory cytokines IL-10 and SOCS3, and of relevant Foxp3, RANKL, and RALDH2 than WT mice, suggesting the role of regulatory T cells in this process. This aggravation of UV-induced inflammation is at least in part attributed to higher extracellular signal-regulated kinase (Erk)1/2 activation and impaired Akt/GSK3β pathways. Subsequent preconditioning experiments using TLR2 ligands at 24 hr before UV irradiation revealed that, surprisingly, pretreatment of TLR1/2 ligand Pam3CSK4, but not lipoteichoic acid, significantly reduced UV-induced inflammation in vivo. Taken together, this study provides an in vivo experimental evidence that UV-induced TLR2 signaling protects against acute UV-induced inflammation.