Regulation of ultraviolet radiation induced cutaneous photoimmunosuppression by Toll-like receptor-4

Abstract

UVB radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, the role of innate immunity on photoimmunological processes has received little attention. The purpose of this study was to determine whether toll-like receptor-4 (TLR4) contributed to UV-induced suppression of contact hypersensitivity (CHS) responses. TLR4−/− and wild type C57BL/6 (TLR4+/+) mice were subjected to a local UVB immunosuppression regimen consisting of 100 mJ/cm2 UVB radiation followed by sensitization with the hapten DNFB. Wild type TLR4+/+ mice exhibited significant suppression of contact hypersensitivity response, whereas TLR4−/− developed significantly less suppression. The suppression in wild type TLR4+/+ mice could be adoptively transferred to naïve syngeneic recipients. Moreover, there were significantly fewer Foxp3 expressing CD4+CD25+ regulatory T-cells in the draining lymph nodes of UV-irradiated TLR4−/− mice than TLR4+/+ mice. When cytokine levels were compared in these two strains after UVB exposure, T-cells from TLR4+/+ mice produced higher levels of IL-10 and TGF-β and lower levels of IFN-γ and IL-17. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous immunosuppression.

Innate Immune Sensors Stimulate Inflammatory and Immunosuppressive Responses to UVB Radiation

“…IL-12 and IL-23 promote the induction of IFN-γ-producing CD8+ TC1 cells and IL-17 CD8+ TC17 cells, respectively, both of which are known to serve as effector cells for CHS responses and to stimulate the synthesis of DNA repair enzymes and reduce CPDs through the NER pathway, suggesting a mechanism for TLR4-induced immunosuppression (Ahmad et al., 2014). This is an extension of their earlier study demonstrating that TLR4 is required for the generation of IL-10-secreting T-regulatory cells that are an essential component of UV-induced immunosuppression (Lewis et al, 2011). Both of these studies stem from an earlier observation that the Lps locus, the same region where the TLR4 gene has been mapped, is critical for the ability of UV radiation to impair DNFB-specific contact hypersensitivity in mice (Yoshikawa and Streilein, 1990).…”

Toll-Like Receptor-4 Deficiency Enhances Repair of UVR-Induced Cutaneous DNA Damage by Nucleotide Excision Repair Mechanism

“…Previous studies have suggested that TLR4 plays an important role in UVB-induced cutaneous immunosuppression (Lewis et al , 2011; Yoshikawa et al 1990; Kurimoto et al , 1994). …”

MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation

“…It has been found that TLR4 plays a role in promoting cutaneous immunosuppression, as TLR4 −/− mice are resistant to the loss of contact hypersensitivity reactions after UV exposure typically observed in susceptible strains of wild type (WT) mice. 2 This TLR4-driven resistance to immunosuppression has been attributed to increased T-regulatory cell function. 2,25 Expression of TLRs 2 and 4 has also been shown to be increased in epidermal cells following UV, and an observed increase in immune signaling molecules, such as MAPK and NF-κB, is dependent on TLR expression.…”

“…2 This TLR4-driven resistance to immunosuppression has been attributed to increased T-regulatory cell function. 2,25 Expression of TLRs 2 and 4 has also been shown to be increased in epidermal cells following UV, and an observed increase in immune signaling molecules, such as MAPK and NF-κB, is dependent on TLR expression. 26 Upon incubation with UV-irradiated KC, these signaling molecules are also up-regulated in Langerhans cells, skin-resident APC, which is dependent on TLRs 2 and 4.…”