Abstract：
The migration of γδ T lymphocytes toward 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 GRP78 is a molecular chaperone that regulates endoplasmic reticulum stress, whereas secretory GRP78, as a member of the resolution-associated molecular patterns, exerts immunoregulatory effects. In this study, we reported that both the intracellular GRP78 in skin lesions and secretory GRP78 in the serum were significantly decreased in patients with psoriasis. A GRP78 knockdown exacerbated imiquimod-induced skin inflammation, whereas the application of recombinant GRP78 protein or BIP inducer X (a GRP78 inducer) attenuated the dermatitis. Mechanistically, the GRP78 knockdown in keratinocytes enhanced the production of chemokines, specifically CCL20, which regulates γδ T-cell migration. Moreover, recombinant GRP78 was found to directly bind to γδ T cells to suppress its migration ability and proinflammatory capacities by downregulating 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.
摘要：
γδT淋巴细胞向皮肤病变的迁移及其伴随的致病性IL-17A的产生在牛皮癣的发病机理中起着至关重要的作用。然而,γδT细胞产生IL-17A及其迁移的调控机制仍有待充分探索。胞内葡萄糖调节蛋白78(GRP78)是调节内质网应激的分子伴侣,而分泌型GRP78作为分辨率相关分子模式的成员，发挥免疫调节作用。这里,我们报道，银屑病患者皮损细胞内GRP78和血清中分泌型GRP78均显著降低。GRP78敲除会加剧IMQ诱导的皮肤炎症，而重组GRP78蛋白或BIX（GRP78诱导剂）的应用会减轻皮炎。机械上,角质形成细胞中的GRP78敲低增强了趋化因子的产生，特别是CCL20，调节γδT细胞迁移。此外，发现重组GRP78直接与γδT细胞结合，通过下调CCR6和IL-17A的表达来抑制其迁移能力和促炎能力。总的来说，我们的结果揭示了GRP78在银屑病发病机制中的关键作用，主要通过调节角质形成细胞与γδT细胞之间的相互作用来发挥，并可能为牛皮癣治疗提供有希望的目标。
