Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Inflammation Program, University of Iowa, Iowa City, Iowa, USA.
J Clin Invest. 2018 May 1;128(5):2042-2047. doi: 10.1172/JCI98446. Epub 2018 Apr 9.
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP-1-mediated inflammation, we took a genetic approach and discovered apoptosis signal-regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
在含有Src 同源区 2（SH2）结构域的磷酸酶 1（SHP-1）羧基末端 Tyr208Asn 氨基酸取代的纯合子小鼠（称为 Ptpn6spin 小鼠）中，自发性地发展出一种类似于人类中性粒细胞性皮肤病的严重炎症性疾病。Ptpn6spin 小鼠的疾病表现为持续的脚垫肿胀和化脓性炎症。最近，除了 IL-1α 和 IL-1R 信号外，我们还证明了几种激酶（如 SYK、RIPK1 和 TAK1）在促进 Ptpn6spin 小鼠炎症性疾病中的关键作用。为了鉴定参与 SHP-1 介导的炎症的新激酶，我们采用了遗传方法，发现凋亡信号调节激酶 1 和 2（ASK1 和 ASK2）是调节 Ptpn6 介导的脚垫炎症的新激酶。ASK1 和 ASK2 的双重缺失消除了 Ptpn6spin 小鼠的皮肤炎症性疾病。这种双重缺失进一步挽救了 Ptpn6spin 小鼠中过度中性粒细胞浸润引起的脾肿大和淋巴结肿大。在机制上，ASK 通过控制中性粒细胞中的促炎信号来调节 Ptpn6spin 介导的疾病。综上所述，本研究确定了 SHP-1 和 ASK 信号转导的相互作用是 IL-1α 驱动的炎症的关键调节剂，并为寻找治疗人类中性粒细胞性皮肤病的新型药物靶点开辟了未来的途径。
