Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis.
Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis.
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SHP2 的变构抑制揭示了 TLR7 的异常运输导致银屑病加重
DOI：
10.15252/emmm.202114455
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发表时间：
2022-03-07
影响因子：
11.1
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Zhu Y;Wu Z;Yan W;Shao F;Ke B;Jiang X;Gao J;Guo W;Lai Y;Ma H;Chen D;Xu Q;Sun Y
银屑病是一种复杂的慢性炎症性皮肤病，分子机制尚不清楚。我们发现Src同源-2结构域蛋白酪氨酸磷酸酶-2（SHP 2）在银屑病患者和咪喹莫特（IMQ）诱导的银屑病样小鼠中均高度表达。此外，SHP 2变构抑制剂SHP 099降低了从银屑病患者采集的PBMC中的促炎细胞因子表达。因此，SHP 099显著改善了小鼠中IMQ触发的皮肤炎症。小鼠皮肤的单细胞RNA测序表明，SHP 2抑制损害骨髓细胞，特别是巨噬细胞中的皮肤炎症。此外，IMQ诱导的银屑病样皮肤炎症在骨髓细胞（单核细胞、成熟巨噬细胞和粒细胞）中显著减轻，但在树突状细胞条件性SHP 2敲除小鼠中则没有。在机制上，SHP 2通过在Tyr 1024处使TLR 7去磷酸化，促进TLR 7的泛素化和NF-κB介导的皮肤炎症，促进TLR 7从高尔基体向巨噬细胞内体的运输。重要的是，在IMQ治疗后，与野生型同窝小鼠相比，Tlr 7点突变敲入小鼠显示出减弱的银屑病样表型。总的来说，我们的研究结果确定了SHP 2作为银屑病的一种新的调节剂，并表明SHP 2抑制可能是银屑病患者的一种有前途的治疗方法。本研究从银屑病患者临床水平、整体动物水平、细胞水平揭示了SHP 2促进TLR 7向内体运输，并通过TLR 7的去磷酸化激活下游NF-κB通路，从而加剧银屑病的发病机制，为银屑病治疗药物的开发提供了潜在靶点。
Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)‐induced psoriasis‐like mice. Also, the SHP2 allosteric inhibitor SHP099 reduced pro‐inflammatory cytokine expression in PBMCs taken from psoriatic patients. Consistently, SHP099 significantly ameliorated IMQ‐triggered skin inflammation in mice. Single‐cell RNA sequencing of murine skin demonstrated that SHP2 inhibition impaired skin inflammation in myeloid cells, especially macrophages. Furthermore, IMQ‐induced psoriasis‐like skin inflammation was significantly alleviated in myeloid cells (monocytes, mature macrophages, and granulocytes)—but not dendritic cells conditional SHP2 knockout mice. Mechanistically, SHP2 promoted the trafficking of toll‐like receptor 7 (TLR7) from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, boosting the ubiquitination of TLR7 and NF‐κB‐mediated skin inflammation. Importantly, Tlr7 point‐mutant knock‐in mice showed an attenuated psoriasis‐like phenotype compared to wild‐type littermates following IMQ treatment. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients. From the clinical level of psoriasis patients, the whole animal level, and the cellular level, this study reveals that SHP2 promotes TLR7 trafficking to endosomes and activates the downstream NF‐κB pathway through dephosphorylation of TLR7, thus exacerbating the pathogenesis of psoriasis and providing a potential target for the development of therapeutic drugs for psoriasis.