Keratinocyte transglutaminase 2 promotes CCR6+ ??T-cell recruitment by upregulating CCL20 in psoriatic inflammation.

ABSTRACT: Keratinocyte-derived cytokines and chemokines amplify psoriatic inflammation by recruiting IL-17-producing CCR6+ ??T-cells and neutrophils. The expression of these cytokines and chemokines mainly depends on NF-?B activity; however, the pathway that activates NF-?B in response to triggering factors is poorly defined. Here, we show that transglutaminase 2 (TG2), previously reported to elicit a TH17 response by increasing IL-6 expression in a mouse model of lung fibrosis, mediates the upregulation of cytokines and chemokines by activating NF-?B in imiquimod (IMQ)-treated keratinocytes. TG2-deficient mice exhibited reduced psoriatic inflammation in skin treated with IMQ but showed systemic immune responses similar to wild-type mice. Experiments in bone marrow (BM) chimeric mice revealed that TG2 is responsible for promoting psoriatic inflammation in non-BM-derived cells. In keratinocytes, IMQ treatment activated TG2, which in turn activated NF-?B signaling, leading to the upregulation of IL-6, CCL20, and CXCL8 and increased leukocyte migration, in vitro. Consequently, TG2-deficient mice showed markedly decreased CCR6+ ??T-cell and neutrophil infiltration in IMQ-treated skin. Moreover, TG2 levels were higher in psoriatic skin than in normal skin and correlated with IL-6, CXCL8, and CCL20 levels. Therefore, these results indicate that keratinocyte TG2 acts as a critical mediator in the amplification of psoriatic inflammation.

SUBMITTER: Shin JW 

PROVIDER: S-EPMC7193648 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature