GRP78 Downregulation in Keratinocytes Promotes Skin Inflammation Via the Recruitment and Activation of CCR6+ IL-17A-producing γδ T Cells

Abstract

The migration of γδ T lymphocytes towards skin lesions and their concomitant pathogenic IL-17A production play a crucial role in the pathogenesis of psoriasis. However, the regulatory mechanisms of IL-17A production by γδ T cells and their migration remain to be fully explored. Intracellular glucose regulated protein 78 (GRP78) is a molecular chaperone that regulates endoplasmic reticulum stress, while secretory GRP78, as a member of the resolution-associated molecular patterns, exerts immunoregulatory effects. Here, we reported that both the intracellular GRP78 in skin lesions and secretory GRP78 in the serum were significantly decreased in psoriasis patients. A GRP78 knockdown exacerbated IMQ-induced skin inflammation while the application of recombinant GRP78 protein or BIX (a GRP78 inducer) attenuated the dermatitis. Mechanistically, the GRP78 knockdown in keratinocytes enhanced the production of chemokines, specifically CCL20, that regulates γδ T cell migration. Moreover, recombinant GRP78 was found to directly bind to γδ T cells to suppress its migration ability and pro-inflammatory capacities by down-regulating the CCR6 and IL-17A expression. Collectively, our results uncovered a pivotal role of GRP78 in the pathogenesis of psoriasis, which was mainly exerted by regulating the interaction between keratinocytes and γδ T cells, and might provide a promising target for psoriasis therapy.