IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice
IL-25 exacerbates autoimmune aortitis in IL-1 receptor antagonist-deficient mice
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DOI：
10.1038/s41598-019-53633-0
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发表时间：
2019-11
影响因子：
4.6
通讯作者：
T. Yoshizaki;S. Itoh;Sachiko Yamaguchi;T. Numata;Aya Nambu;N. Kimura;H. Suto;K. Okumura;K. Sudo;A. Yamaguchi;S. Nakae
中科院分区：
文献类型：
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作者：
T. Yoshizaki;S. Itoh;Sachiko Yamaguchi;T. Numata;Aya Nambu;N. Kimura;H. Suto;K. Okumura;K. Sudo;A. Yamaguchi;S. Nakae
IL-25是细胞因子IL-17家族的成员，已知其增强2型免疫应答，但抑制3型（IL-17 A）介导的免疫应答。缺乏IL-1受体拮抗剂的小鼠（Il 1 rn −/−小鼠）具有过量的IL-1信号传导，导致自发发生IL-1-、TNF-和IL-17 A依赖性肠炎。我们发现IL-25 mRNA在IL-1 rn −/−小鼠的脾脏中表达增加，这表明IL-25可能通过抑制3型介导的免疫应答来抑制IL-1、TNF和IL-17 A依赖性乳腺炎的发生。然而，我们出乎意料地发现，与Il 1 rn −/−小鼠相比，Il 25 −/− Il 1 rn −/−小鼠的炎症发展减弱，伴随着树突状细胞、巨噬细胞和中性粒细胞等炎性细胞的积聚减少，局部病变中Il 17 a和TNF a的mRNA表达减少，但Il 4或Il 13的mRNA表达没有减少。组织来源的IL-25而非免疫细胞来源的IL-25对乳腺炎的发展至关重要。IL-25分别增强IL-25受体表达树突状细胞和巨噬细胞在IL-1 rn −/−小鼠脾脏炎症部位产生IL-1β和TNF，导致这些小鼠IL-1、TNF和IL-17 A依赖性乳腺炎的恶化。我们的研究结果表明，IL-25的中和可能是一个潜在的治疗靶点的乳腺炎。
IL-25, a member of the IL-17 family of cytokines, is known to enhance type 2 immune responses, but suppress type 3 (IL-17A)-mediated immune responses. Mice deficient in IL-1 receptor antagonist (Il1rn−/−mice) have excessive IL-1 signaling, resulting in spontaneous development of IL-1–, TNF– and IL-17A–dependent aortitis. We found that expression ofII25mRNA was increased in the aortae ofIl1rn−/−mice, suggesting that IL-25 may suppress development of IL-1–, TNF– and IL-17A–dependent aortitis inIl1rn−/−mice by inhibiting type 3-mediated immune responses. However, we unexpectedly found thatIl25−/−Il1rn−/−mice showed attenuated development of aortitis, accompanied by reduced accumulation of inflammatory cells such as dendritic cells, macrophages and neutrophils and reduced mRNA expression ofIl17aandTnfa—but notIl4orIl13—in local lesions compared withIl1rn−/−mice. Tissue–, but not immune cell–, derived IL-25 was crucial for development of aortitis. IL-25 enhanced IL-1β and TNF production by IL-25 receptor–expressing dendritic cells and macrophages, respectively, at inflammatory sites of aortae ofIl1rn−/−mice, contributing to exacerbation of development of IL-1–, TNF– and IL-17A–dependent aortitis in those mice. Our findings suggest that neutralization of IL-25 may be a potential therapeutic target for aortitis.