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S1PR4-dependent CCL2 production promotes macrophage recruitment in a murine psoriasis model.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-02-04 , DOI: 10.1002/eji.201948349 Christian Schuster 1 , Arnaud Huard 1 , Evelyn Sirait-Fischer 1 , Christina Dillmann 1 , Bernhard Brüne 1, 2, 3, 4 , Andreas Weigert 1, 3, 4
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-02-04 , DOI: 10.1002/eji.201948349 Christian Schuster 1 , Arnaud Huard 1 , Evelyn Sirait-Fischer 1 , Christina Dillmann 1 , Bernhard Brüne 1, 2, 3, 4 , Andreas Weigert 1, 3, 4
Affiliation
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The sphingolipid sphingosine‐1‐phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein‐coupled receptors. The immune cell‐specific sphingosine‐1‐phosphate receptor 4 (S1pr4) was connected to the generation of IL‐17‐producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod‐induced murine psoriasis via regulation of IL‐17 production. We did not observe altered IL‐17 production, although psoriasis severity was reduced in S1pr4‐deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL‐6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan‐A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF‐κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.
中文翻译：
依赖S1PR4的CCL2的产生促进了小鼠牛皮癣模型中巨噬细胞的募集。
鞘脂鞘氨醇-1-磷酸（S1P）通过与五个G蛋白偶联受体结合来实现免疫细胞生物学中的独特功能。免疫细胞特异性鞘氨醇-1-磷酸受体4（S1pr4）通过调节先天免疫细胞中细胞因子的产生与产生IL-17的T细胞产生联系。因此，我们探讨了S1pr4是否通过调节IL-17的产生影响咪喹莫特诱导的鼠类牛皮癣。尽管在S1pr4缺陷型小鼠中牛皮癣的严重程度有所降低，但我们并未观察到IL-17产生的变化。取而代之的是，S1pr4的消融减弱了CCL2，IL-6和CXCL1的产生，并随后减少了浸润的单核细胞和粒细胞的数量。在Zymosan-A诱发的腹膜炎中也观察到S1pr4，CCL2和Mϕ浸润之间存在联系。缺乏S1pr4时，Boyden室迁移分析功能性地联系了鼠皮肤中CCL2的产生减少和单核细胞迁移的减弱。从机制上讲，S1pr4信号传导与驻留Mϕs中的TLR信号传导协同产生CCL2，可能是通过NF-κB途径。我们建议S1pr4激活增强常驻Mϕ的TLR反应，以增加CCL2的产生，从而吸引更多的Mϕ。因此，S1pr4可能是减少永久性炎症反应的目标。
更新日期：2020-02-04
中文翻译：
依赖S1PR4的CCL2的产生促进了小鼠牛皮癣模型中巨噬细胞的募集。
鞘脂鞘氨醇-1-磷酸（S1P）通过与五个G蛋白偶联受体结合来实现免疫细胞生物学中的独特功能。免疫细胞特异性鞘氨醇-1-磷酸受体4（S1pr4）通过调节先天免疫细胞中细胞因子的产生与产生IL-17的T细胞产生联系。因此，我们探讨了S1pr4是否通过调节IL-17的产生影响咪喹莫特诱导的鼠类牛皮癣。尽管在S1pr4缺陷型小鼠中牛皮癣的严重程度有所降低，但我们并未观察到IL-17产生的变化。取而代之的是，S1pr4的消融减弱了CCL2，IL-6和CXCL1的产生，并随后减少了浸润的单核细胞和粒细胞的数量。在Zymosan-A诱发的腹膜炎中也观察到S1pr4，CCL2和Mϕ浸润之间存在联系。缺乏S1pr4时，Boyden室迁移分析功能性地联系了鼠皮肤中CCL2的产生减少和单核细胞迁移的减弱。从机制上讲，S1pr4信号传导与驻留Mϕs中的TLR信号传导协同产生CCL2，可能是通过NF-κB途径。我们建议S1pr4激活增强常驻Mϕ的TLR反应，以增加CCL2的产生，从而吸引更多的Mϕ。因此，S1pr4可能是减少永久性炎症反应的目标。
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