Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation
Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation
复制标题
角质形成细胞基于自噬的 HMGB1 非常规分泌在银屑病皮肤炎症中发挥着关键作用
DOI：
10.1080/15548627.2020.1725381
复制
发表时间：
2020-02-18
期刊：
影响因子：
13.3
通讯作者：
Li, Jiong
中科院分区：
文献类型：
--
作者：
Wang, Zhen;Zhou, Hong;Li, Jiong
巨噬/自噬影响牛皮癣的确切机制尚不清楚。在这里，我们发现角化细胞（KC）自噬与患者和小鼠模型中的银屑病严重程度呈正相关，并且可以通过丝裂原活化蛋白激酶（MAPK）家族失活来抑制。自噬通量受损可减轻银屑病样炎症。我们还发现基于自噬的非常规分泌途径（自分泌）依赖于ATG5（自噬相关5）和GORASP2（高尔基重组堆积蛋白2）促进牛皮癣样KC炎症。此外，警报蛋白HMGB1（高迁移率组1）在调节银屑病样皮肤炎症方面比其他自身分泌蛋白更有效。HMGB1在自噬高效KCs中的中和消除了Krt14(+/+)-Atg5(f/f) KCs和Krt14(Cre/+) -Atg5(f/f) KCs之间银屑病炎症的差异，相反，重组HMGB1在体内几乎完全恢复了Krt14(Cre/+) -Atg5(f/f) KCs的银屑病炎症。这些结果表明，hmgb1相关的自身分泌在皮肤炎症中起关键作用。最后，我们证明了Krt14(Cre/+)-hmgb1（f/f）小鼠表现出减轻的银屑病炎症，这是由于kc特异性hmgb1相关的自身分泌和γ δ T细胞之间的必要串音。因此，本研究揭示了银屑病发病机制中的一种新的自噬机制，提示研究和治疗银屑病具有重要的临床意义。
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(+/+)-Atg5(f/f) KCs and Krt14(Cre/+)-atg5(f/f) KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in Krt14(Cre/+)-atg5(f/f) KCs in vivo. These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inflammation. Finally, we demonstrated that Krt14(Cre/+)-hmgb1(f/f) mice displayed attenuated psoriatic inflammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and gamma delta T cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis.