Contribution of Trem2 Signaling to the Development of Painful Diabetic Neuropathy by Mediating Microglial Polarization in Mice [post]

Xin Chen, Yue Le, Wan-you He, Jian He, Yun-hua Wang, Lei Zhang, Qing-ming Xiong, Xue-qin Zheng, Han-bing Wang
2021 unpublished
Background Painful diabetic neuropathy (PDN) is a common and intractable complication of diabetes mellitus, with little effective treatment. PDN has been associated with spinal neuroinflammation characterized by microglial activation. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), specifically localized on microglia, has been identified as a vital factor in modulating neuroinflammation and microglial phenotypes in neural diseases. Therefore, we hypothesized that spinal
more » ... REM2 might contribute to PDN and neuroinflammation by regulating microglial activity and phenotypes. Methods Type I diabetes mellitus was elicited by a single intraperitoneal administration of streptozotocin (STZ) in mice. The pain behaviors were reflected by paw mechanical withdrawal thresholds (PMWT) and thermal withdrawal latency (PTWL). Results We demonstrated that up-regulation of microglial TREM2 and amplification of both microglial M1 and M2 response was along with the presence of diabetes-related mechanical allodynia and thermal hypersensitivity. Moreover, we found that overexpression of TREM2 in microglia aggravated the symptom of PDN, amplified microglia M1 response, and suppressed microglia M2 polarization in the lumbar spinal cord of diabetic mice. However, inhibition of TREM2 with anti-TREM2 neutralizing antibodies attenuated mechanical allodynia and thermal hyperalgesia in diabetic mice. Besides, we identified Galectin-3 (GLT-3) as the potential ligand of the TREM2 receptor in facilitating the progression of PDN. Conclusions TREM2 could be a critical microglial membrane molecule that modulates microglial phenotypes pain hypersensitivity in PDN. GLT-3 might act as a specific ligand to trigger TREM2 signaling in PDN or other neuropathic pain.
doi:10.21203/rs.3.rs-671471/v1 fatcat:4jnm322jzzhu5c6mkxfw3zuih4