Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization

Area of Science:

• Neuroscience
• Immunology
• Pain Research

Background:

• Chronic migraine is a debilitating condition with poorly understood mechanisms and limited treatment options.
• The trigeminovascular pathway is implicated in migraine pathophysiology, involving activation and sensitization of primary afferent neurons.
• Chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 signaling are known to mediate chronic pain development.

Purpose of the Study:

• To investigate the role of the CCL2-CCR2 signaling pathway in the development of chronic migraine.
• To identify the cellular sources of CCL2 and CCR2 involved in chronic headache.
• To evaluate the therapeutic potential of targeting the CCL2-CCR2 pathway, alone or in combination with CGRP inhibition.

Main Methods:

• Chronic headache was modeled in mice using repeated administration of nitroglycerin (NTG) and restraint stress.
• Global knockout mice for Ccl2 and Ccr2 were used to assess the necessity of this pathway.
• CCL2 neutralizing antibodies and genetic deletion of CCR2 in specific cell types (T cells, myeloid cells, primary afferent neurons) were employed.
• Expression levels of CCL2 and CCR2, and neuronal responses to CGRP and PACAP were analyzed.

Main Results:

• Repeated NTG administration upregulated Ccl2 and Ccr2 mRNA in dura and trigeminal ganglion (TG) tissues.
• Ccl2 and Ccr2 global knockout mice did not develop NTG-induced hypersensitivity, and CCL2 antibody treatment inhibited headache behaviors.
• CCR2 was expressed in macrophages and T cells, not TG neurons; eliminating CCR2 in T cells or myeloid cells abolished NTG-induced behaviors.
• NTG increased TG neuron responses to CGRP and PACAP in wild-type but not Ccr2 knockout mice.
• Co-administration of CCL2 and CGRP neutralizing antibodies was more effective than individual antibodies in reversing headache behaviors.

Conclusions:

• Peripheral CCL2-CCR2 signaling in macrophages and T cells is crucial for establishing chronic headache-related sensitization.
• This pathway enhances CGRP and PACAP signaling in TG neurons, leading to persistent neuronal sensitization.
• The CCL2-CCR2 pathway represents a potential therapeutic target for chronic migraine, with combined inhibition of CCL2-CCR2 and CGRP showing enhanced efficacy.