Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation

Zhen Wang, Hong Zhou, Huaping Zheng, Xikun Zhou, Guobo Shen, Xiu Teng, Xiao Liu, Jun Zhang, Xiaoqiong Wei, Zhonglan Hu, Fanlian Zeng, Yawen Hu, Jing Hu, Xiaoyan Wang, Shuwen Chen, Juan Cheng, Chen Zhang, Yiyue Gui, Song Zou, Yan Hao, Qixiang Zhao, Wenling Wu, Yifan Zhou, Kaijun Cui, Nongyu Huang, Yuquan Wei, Wei Li, Jiong Li
Autophagy 2020 February 4
The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was positively correlated with psoriatic severity in patients and mouse models and could be inhibited by mitogen-activated protein kinase (MAPK) family inactivation. The impairment of autophagic flux alleviated psoriasisform inflammation. We also found that an autophagy-based unconventional secretory pathway (autosecretion) dependent on ATG5 (autophagy related 5) and GORASP2 (golgi reassembly stacking protein 2) promoted psoriasiform KC inflammation. Moreover, the alarmin HMGB1 (high mobility group box 1) was more effective than other autosecretory proteins in regulating psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs eliminated the differences in psoriasiform inflammation between Krt14+/+ -Atg5f/f KCs and Krt14Cre/+ -atg5f/f KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in Krt14Cre/+ -atg5f/f KCs in vivo . These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inflammation. Finally, we demonstrated that Krt14Cre/+ -hmgb1f/f mice displayed attenuated psoriatic inflammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis.

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