Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model

Abstract

Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. Results The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

“…TREM2 knockout alveolar macrophages displayed augmented bacterial phagocytosis in vitro and in vivo compared to WT alveolar macrophages [ 34 ]. On the other hand, researchers have found that TREM2 suppresses inflammation by attenuating microglial activation [ 32 ], suppressing PI3K/NFκB signaling [ 35 , 36 ], downregulating TLR signaling [ 37 , 38 , 39 ], and modulating the TREM2-autophagy axis [ 39 ]. TREM2 also modifies the microglial phenotype and provides neuroprotection in P301S tau transgenic mice [ 40 ].…”

The Role of Autophagy and Apoptosis in Neuropathic Pain Formation

“…However, there is no direct evidence that inhibition of apoptotic activities in the injured neurons can attenuate pain behavior. In contrast to apoptosis, many studies with different animal models have shown changed autophagic activities in the injured nerve [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ], spinal cord [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], and even brain [ 43 ] after nerve injury. These studies also showed that upregulated autophagic activities can directly alleviate neuropathic pain [ 24 , 26 , 27 , 32 , 33 , 37 , 38 ].…”

Resveratrol Can Attenuate Astrocyte Activation to Treat Spinal Cord Injury by Inhibiting Inflammatory Responses

“… [ 92 ] Neuropathic pain Sprague Dawley rats Rats constructed for neuropathic pain were treated with RSV by intraperitoneal injection (300 ug/day) RSV reduced neuroinflammation and neuropathic pain in rats by inhibiting autophagy via downregulating the TREM2 signaling pathway. [ 93 ] …”

“…All these functions of RSV aid repress the instigation and development of inflammation. Moreover, studies have shown that RSV could improve autophagy [ 93 ] when inflammation occurs.…”