PDF(Pubmed)
Abstract：
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
摘要：
细胞因子使用下游Janus激酶(JAK)来促进慢性炎性疾病。JAK1依赖性2型细胞因子驱动过敏性炎症，具有JAK1功能获得(GoF)变异体的患者会发生特应性皮炎(AD)和哮喘.为了探索组织特异性功能，我们将人JAK1GoF变异体(JAK1GoF)插入小鼠体内,观察到自发性AD样皮肤病的发展,但当JAK1GoF的表达被限制在基质区时,对肺部炎症有意想不到的抵抗.我们确定了JAK1在迷走神经感觉神经元中抑制气道炎症的作用。此外,Calcb/CGRPβ的表达依赖于迷走神经中的JAK1，CGRPβ抑制第2组固有淋巴细胞功能和过敏性气道炎症。我们的发现揭示了JAK1在跨组织的感觉神经元中的进化保守但不同的功能。这种生物学特性提高了治疗性JAK抑制剂可能进一步优化组织特异性功效的可能性，以增强未来的精准医学。
