Abstract：
IL-13 signaling polarizes macrophages to an M2 alternatively activated phenotype, which regulates tissue repair and anti-inflammatory responses. However, an excessive activation of this pathway leads to severe pathologies, such as allergic airway inflammation and asthma. In this work, we identified NOTCH4 receptor as an important modulator of M2 macrophage activation. We show that the expression of NOTCH4 is induced by IL-13, mediated by Janus kinases and AP1 activity, probably mediated by the IL-13Rα1 and IL-13Rα2 signaling pathway. Furthermore, we demonstrate an important role for NOTCH4 signaling in the IL-13 induced gene expression program in macrophages, including various genes that contribute to pathogenesis of the airways in asthma, such as ARG1, YM1, CCL24, IL-10, or CD-163. We also demonstrate that NOTCH4 signaling modulates IL-13-induced gene expression by increasing IRF4 activity, mediated, at least in part, by the expression of the histone H3K27me3 demethylase JMJD3, and by increasing AP1-dependent transcription. In summary, our results provide evidence for an important role of NOTCH4 signaling in alternative activation of macrophages by IL-13 and suggest that NOTCH4 may contribute to the increased severity of lesions in M2 inflammatory responses, such as allergic asthma, which points to NOTCH4 as a potential new target for the treatment of these pathologies.
摘要：
IL-13信号传导将巨噬细胞极化为M2交替激活的表型，调节组织修复和抗炎反应。然而,这种途径的过度激活会导致严重的病理，如过敏性气道炎症和哮喘。在这项工作中,我们确定NOTCH4受体是M2巨噬细胞激活的重要调节剂。我们表明，NOTCH4的表达是由IL-13诱导的，由Janus激酶和AP1活性介导，可能由IL-13Rα1和IL-13Rα2信号通路介导。此外，我们证明了NOTCH4信号在IL-13诱导的巨噬细胞基因表达程序中的重要作用，包括导致哮喘气道发病的各种基因，例如ARG1、YM1、CCL24、IL-10或CD-163。我们还证明，NOTCH4信号通过增加IRF4活性来调节IL13诱导的基因表达，mediated,至少在某种程度上,通过表达组蛋白H3K27me3去甲基酶JMJD3，并通过增加AP1依赖性转录。总之,我们的研究结果为NOTCH4信号传导在IL-13激活巨噬细胞中的重要作用提供了证据，并表明NOTCH4可能有助于M2炎症反应中病变的严重程度增加，比如过敏性哮喘，这表明NOTCH4是治疗这些疾病的潜在新靶点。
