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bioRxiv · 10.1101/2021.01.09.426056

Epidermal TRPV4 ion channels regulate UVB induced sunburn by triggering inflammmasome activation and MAPK signaling

Moore, C.·Choi, S.·Moon, G.·Zhang, J.·Chen, Y.·Liedtke, W.
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Abstract

Skin inflammation is an evolutionary-honed protective mechanism that serves to clear noxious cues and irritants and initiate regeneration. Calcium-permeable transient-receptor-potential (TRP) ion channels have critical functions in sensory transduction which is sensitized in skin inflammation. Skin sensory transduction relies on skin-innervating sensory neurons in the dorsal root ganglion (DRG), but also on innervated keratinocytes (KC). The multimodally-activated TRPV4 is robustly expressed in KC, where it can readily be activated by Ultraviolet-B (UVB). Our goal was to deconstruct keratinocyte TRPV4-mediated signaling, specifically how TRPV4 can facilitate inflammatory injury, thus lowering pain thresholds and rendering KC into pain-generator cells. We wanted to uncover the effect of TRPV4-mediated signaling on UVB-induced inflammasome activation in KC given the powerful impact of the activated inflammasome on pro-inflammatory/pro-algesic secretory signaling, using mouse models and cultured human KC. In mice, our evidence suggests that TRPV4 functions as calcium-permeable channel upstream of the KC inflammasome. Furthermore, we found that UVB induced activation of TRPV4 caused rapid - within minutes - Extracellular Signal Regulated Kinase (ERK) phosphorylation, caspase-1 activation and Interleukin-1{beta} (IL-1{beta}) secretion. In human primary KC we demonstrated that UVB induced secretion of IL-1{beta} was dependent on the NLR family pyrin domain containing 1 (NLRP1) inflammasome. Direct chemical TRPV4 activation could also activate NLRP1 and to lesser extent NLPR3. Building on our previous work, we now define at increased resolution TPRV4-dependent forefront signaling mechanisms in KC in response to UVB, showing TRPV4 upstream of the NLRP1 inflammasome, subsequent rapid ERK activation and pro-inflammatory/pro-algesic secretory function.

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Moore, C., Choi, S., Moon, G., Zhang, J., Chen, Y., Liedtke, W.. 2021-01-10. Epidermal TRPV4 ion channels regulate UVB induced sunburn by triggering inflammmasome activation and MAPK signaling. https://doi.org/10.1101/2021.01.09.426056

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