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CD8+T 细胞衍生的 IL-13 增加巨噬细胞 IL-10 以缓解神经病理性疼痛。

CD8+ T cell-derived IL-13 increases macrophage IL-10 to resolve neuropathic pain.

机构信息

Laboratories of Neuroimmunology, Department of Symptom Research, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Department of Biological Sciences, Knoebel Institute for Healthy Aging, University of Denver, Denver, Colorado, USA.

出版信息

JCI Insight. 2022 Mar 8;7(5):e154194. doi: 10.1172/jci.insight.154194.

DOI:10.1172/jci.insight.154194
PMID:35260535
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8983134/
Abstract

Understanding the endogenous mechanisms regulating resolution of pain may identify novel targets for treatment of chronic pain. Resolution of chemotherapy-induced peripheral neuropathy (CIPN) after treatment completion depends on CD8+ T cells and on IL-10 produced by other cells. Using Rag2-/- mice lacking T and B cells and adoptive transfer of Il13-/- CD8+ T cells, we showed that CD8+ T cells producing IL-13 were required for resolution of CIPN. Intrathecal administration of anti-IL-13 delayed resolution of CIPN and reduced IL-10 production by dorsal root ganglion macrophages. Depleting local CD206+ macrophages also delayed resolution of CIPN. In vitro, TIM3+CD8+ T cells cultured with cisplatin, apoptotic cells, or phosphatidylserine liposomes produced IL-13, which induced IL-10 in macrophages. In vivo, resolution of CIPN was delayed by intrathecal administration of anti-TIM3. Resolution was also delayed in Rag2-/- mice reconstituted with Havcr2 (TIM3)-/- CD8+ T cells. Our data indicated that cell damage induced by cisplatin activated TIM3 on CD8+ T cells, leading to increased IL-13 production, which in turn induced macrophage IL-10 production and resolution of CIPN. Development of exogenous activators of the IL-13/IL-10 pain resolution pathway may provide a way to treat the underlying cause of chronic pain.

摘要

了解调节疼痛缓解的内源性机制可能为治疗慢性疼痛确定新的靶点。化疗诱导的周围神经病变（CIPN）在治疗完成后缓解取决于 CD8+T 细胞和其他细胞产生的 IL-10。使用缺乏 T 和 B 细胞的 Rag2-/-小鼠和过继转移 Il13-/-CD8+T 细胞，我们表明产生 IL-13 的 CD8+T 细胞是 CIPN 缓解所必需的。鞘内给予抗 IL-13 延迟了 CIPN 的缓解，并减少了背根神经节巨噬细胞产生的 IL-10。耗尽局部 CD206+巨噬细胞也延迟了 CIPN 的缓解。在体外，用顺铂、凋亡细胞或磷脂酰丝氨酸脂质体培养的 TIM3+CD8+T 细胞产生 IL-13，后者诱导巨噬细胞产生 IL-10。在体内，鞘内给予抗 TIM3 延迟了 CIPN 的缓解。在用 Havcr2（TIM3）-/-CD8+T 细胞重建的 Rag2-/-小鼠中，CIPN 的缓解也被延迟。我们的数据表明，顺铂诱导的细胞损伤激活了 CD8+T 细胞上的 TIM3，导致 IL-13 产生增加，进而诱导巨噬细胞产生 IL-10 和缓解 CIPN。开发外源性激活物的 IL-13/IL-10 疼痛缓解途径可能为治疗慢性疼痛的根本原因提供一种方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/8f7de8c6a3c6/jciinsight-7-154194-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/c84d036bf441/jciinsight-7-154194-g116.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/403a9ff85fa1/jciinsight-7-154194-g117.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/ea2a12dc38aa/jciinsight-7-154194-g118.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/841fea5d2d1d/jciinsight-7-154194-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/705f0d58b2bb/jciinsight-7-154194-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/8f7de8c6a3c6/jciinsight-7-154194-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/c84d036bf441/jciinsight-7-154194-g116.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/403a9ff85fa1/jciinsight-7-154194-g117.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/ea2a12dc38aa/jciinsight-7-154194-g118.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/841fea5d2d1d/jciinsight-7-154194-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/705f0d58b2bb/jciinsight-7-154194-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8983134/8f7de8c6a3c6/jciinsight-7-154194-g121.jpg

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