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.
Highlights
Macrophages play key roles in the pathogenesis and regulation of the inflammatory reaction [1]
We showed the quantification of Iba-1 and GFAP immunoreactivities, in comparison with the WT and Arginase 2 (Arg2) KO at corresponding times (Figure 4C,D), which show larger values for the Arg2 KO group compared to the WT group at every time point and confirmed that the largest values were reached on day 7 post-surgery in each group
This study investigated the effect of Arg2 deficiency on the inflammatory condition in the spinal cord and pain state of mice with a spinal nerve transection (SNT) neuropathic pain model
Summary
Macrophages play key roles in the pathogenesis and regulation of the inflammatory reaction [1]. When macrophages are prone to release pro-inflammatory cytokines, they contribute to the development of inflammation and are classified as M1 macrophages They are considered M2 macrophages when they produce anti-inflammatory mediators and potentiate cell proliferation, tissue repair, and the healing process [3]. In M1 macrophages, L-arginine is metabolized to nitric oxide (NO) and citrulline under the action of nitric oxide synthase (NOS) expressed by the M1 phenotype This pathway prevents cell proliferation, causes cellular toxicity, and facilitates inflammation. M2 macrophages with strong expression of arginase, which hydrolyzes L-arginine to ornithine and urea, contribute to cell proliferation and resolution of inflammation Both NO and ornithine are generated from the same L-arginine cellular substrate by NOS and arginase, respectively. It has been demonstrated in many studies of various diseases that arginase via arginine/ornithine metabolism reduces the production of NO via NOS, by limiting the availability of the L-arginine cellular substrate and subsequently impairing the inflammatory state [4,5]
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