TREM2 activation suppresses central sensitisation by promoting autophagy in a chronic migraine model with recurrent nitroglycerin stimulation in mice.

Abstract

BACKGROUND AND PURPOSE: Microglial activation plays a role in driving chronic migraine (CM). Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in brain microglia and impacts neuroinflammation in nervous system diseases. However, its role in CM is unclear. Here, we have investigated the role of microglial TREM2 in the development of CM. EXPERIMENTAL APPROACH: We used male mice receiving repeated intraperitoneal nitroglycerin (NTG) injections as a CM model. Mechanical and thermal hypersensitivity were assessed by mechanical withdrawal threshold and thermal withdrawal latency. TREM2 knockout mice (TREM2) and systemically administered TREM2 agonist COG1410 were evaluated for TREM2's role in CM. TREM2, calcitonin gene-related peptide (CGRP) and c-fos expression in the trigeminal nucleus caudalis (TNC) were measured for central sensitisation assessment. Immunohistochemical analyses and western blots measured protein expression in the TNC and BV-2 microglia. Quantitative real-time polymerase chain reaction (qRT-PCR) detected inflammatory factor expression. KEY RESULTS: Recurrent NTG injection up-regulated TNC protein levels of TREM2, CGRP and c-fos. TREM2 loss accelerated NTG-induced CM development, increased CGRP and c-fos expression, and inhibited TNC autophagy. Conversely, COG1410 prevented hyperalgesia and reduced CGRP/c-fos expression in the TNC after recurrent NTG administration. In vitro, TREM2 knockdown enhanced the expression of inflammation-related genes and the mTOR/p70s6k pathway activation in lipopolysaccharide (LPS)-stimulated BV-2 microglia, whereas COG1410 significantly inhibited LPS-induced mTOR/p70s6k pathway activation and alleviated inflammatory responses. CONCLUSION AND IMPLICATIONS: These data show that TREM2 plays a protective role in CM by modulating microglial activation and autophagy in the TNC via the mTOR/p70s6k pathway.