CGRP受体拮抗作用损害小胶质细胞抗炎功能：补充IL-4作为偏头痛的补偿策略
CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.
摘要(中文译文)
降钙素基因相关肽（CGRP）是偏头痛的关键治疗靶点，但其在中枢神经免疫调节中的双重作用尚不完全清楚。这项研究揭示了一个关键的悖论：虽然CGRP在体外直接促进小胶质细胞的抗炎激活，但在慢性偏头痛小鼠模型中用CGRP受体拮抗剂BIBN4096BS治疗可以迅速缓解疼痛，但并没有伴随着小胶质细胞抗炎标志物的增加，包括CD206和p-STAT6。这一发现表明，完全阻断CGRP可能会无意中减弱被掩盖的内源性促修复张力。为了补充这种信号，我们引入了IL-4干预。IL-4不仅通过STAT6通路激活恢复了小胶质细胞的抗炎功能，而且与CGRP拮抗剂联合使用时也产生了协同镇痛作用，优于单一疗法。STAT6过表达进一步增强了CGRP和IL-4组合的抗炎作用，而STAT6敲除完全逆转了这种保护作用。这些发现表明，CGRP拮抗作用在提供快速镇痛的同时，可能以抑制神经免疫修复为代价。将CGRP拮抗与STAT6通路激活相结合，可以提供一种同时阻断血管源性疼痛和支持免疫稳态的策略，为偏头痛治疗提供新的概念框架。
Abstract
Calcitonin gene-related peptide (CGRP) is a key therapeutic target for migraine, yet its dual role in central neuroimmune regulation remains incompletely understood. This study reveals a critical paradox: while CGRP directly promotes anti-inflammatory activation of microglia in vitro, treatment with the CGRP receptor antagonist BIBN4096BS in a chronic migraine mouse model rapidly alleviated pain but was not accompanied by an increase in microglial anti-inflammatory markers, including CD206 and p-STAT6. This finding suggests that complete CGRP blockade may inadvertently attenuate a masked endogenous pro-repair tone. To supplement this signaling, we introduced IL-4 intervention. IL-4 not only restored microglial anti-inflammatory function via STAT6 pathway activation but also produced synergistic analgesic effects when combined with the CGRP antagonist, superior to either monotherapy. STAT6 overexpression further enhanced the anti-inflammatory effect of the CGRP and IL-4 combination, while STAT6 knockdown completely reversed this protective effect. These findings demonstrate that CGRP antagonism, while providing rapid analgesia, may come at the cost of suppressing neuroimmune repair. Combining CGRP antagonism with STAT6 pathway activation may offer a strategy to simultaneously block vasogenic pain and support immune homeostasis, providing a new conceptual framework for migraine therapy.
如何引用
AMA
Zichao Li, Dan-Li, Zhen-Zhen Fan, Hong-Bin Cai, Zhao-Ming Ge. CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.. Brain, behavior, and immunity. 2026; doi:10.1016/j.bbi.2026.106973.
APA
Zichao Li, Dan-Li, Zhen-Zhen Fan, Hong-Bin Cai, Zhao-Ming Ge (2026). CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.. Brain, behavior, and immunity. https://doi.org/10.1016/j.bbi.2026.106973
GB/T 7714
Zichao Li, Dan-Li, Zhen-Zhen Fan, Hong-Bin Cai, Zhao-Ming Ge. CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.[J]. Brain, behavior, and immunity, 2026 doi:10.1016/j.bbi.2026.106973.
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