Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice

Abstract

Microglia, the resident macrophages, act as the first and main form of active immune defense in the central nervous system. Arginase 2 (Arg2) is an enzyme involved in L-arginine metabolism and is expressed in macrophages and nervous tissue. In this study, we determined whether the absence of Arg2 plays a beneficial or detrimental role in the neuroinflammatory process. We then investigated whether the loss of Arg2 potentiated microglia activation and pain behaviors following nerve injury-induced neuropathic pain. A spinal nerve transection (SNT) experimental model was used to induce neuropathic pain in mice. As a result of the peripheral nerve injury, SNT induced microgliosis and astrogliosis in the spinal cord, and upregulated inflammatory signals in both wild-type (WT) and Arg2 knockout (KO) mice. Notably, inflammation increased significantly in the Arg2 KO group compared to the WT group. We also observed a more robust microgliosis and a lower mechanical threshold in the Arg2 KO group than those in the WT group. Furthermore, our data revealed a stronger upregulation of M1 pro-inflammatory cytokines, such as interleukin (IL)-1β, and a stronger downregulation of M2 anti-inflammatory cytokines, including IL4 and IL-10, in Arg2 KO mice. Additionally, stronger formation of enzyme-inducible nitric oxide synthase, oxidative stress, and decreased expression of CD206 were detected in the Arg2 KO group compared to the WT group. These results suggest that Arg2 deficiency contributes to inflammatory response. The reduction or the loss of Arg2 results in the stronger neuroinflammation in the spinal dorsal horn, followed by more severe pain behaviors arising from nerve injury-induced neuropathic pain.

CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation

“…The correlation between neuropathic pain and microglia is well established, with strong evidence of both morphological and pathological mechanisms of disease [7]. In the spinal nerve ligation (SNL) rat model, the microglia in the dorsal horn of the spinal cord showed significant changes in morphology and in the number of spots staining with specific microglial markers [8][9][10][11].…”

Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype

“…Arg2 is a mitochondrial protein involved in arginine metabolism; however, we and other investigators have shown that its role in macrophages goes beyond its enzymatic activity and places Arg2 as a key player in the resolution of the inflammatory response in these innate immune cells. 7 , 25 , 26 Therefore, increasing Arg2 levels in macrophages could represent an alternative route for the treatment of inflammatory disorders. The over-expression of proteins could be achieved in multiple ways, for example, by using viral vectors 27 or by optimizing mechanisms at the post-transcriptional level, including mRNA degradation by miRNAs.…”

“…In this study, we also observed a generalized decrease of other pro-inflammatory cytokines such as IL-6 and TNF upon treatment with Arg2 TSB. The biological mechanisms behind this broader effect are unknown; however, Arg2 knock-out mice have previously reported to have higher TNF-α levels compared with wild type (WT) in response to Helicobacter pylori infection 25 and express higher mRNA levels of IL-1β as well as Nos2 (which leads to production and secretion of the pro-inflammatory mediator nitric oxide) in a model of nerve injury, 26 while the over-expression of Arg2 led to a decrease of inducible nitric oxide protein levels in LPS-stimulated RAW 264.7 cells. 31 This evidence collectively suggests a pleiotropic role for Arg2 in cytokines secretion and inflammatory signaling.…”

Adrenomedullin is an Important Pathological Mediator in Progression of Chronic Neuropathic Pain

“…Nitric oxide which is produced by L-arginine catalyzed by nitric oxide synthase, is a small, highly soluble and diffusible free radical, which is an important signal molecule between nerve cells. As a neuronal synthase, nNOS has been proved to play a role in neuropathic pain by generous studies [37,38]. In peripheral nerve injury, NMDAR [39,40] is activated in advance to promote the opening of Ca 2+ channel [41], and then activate nNOS to synthesize NO.…”