Polarization of Microglia to the M2 Phenotype in a Peroxisome Proliferator-Activated Receptor Gamma–Dependent Manner Attenuates Axonal Injury Induced by Traumatic Brain Injury in Mice

Abstract

Increasing evidence indicates that activated microglia play an important role in the inflammatory response following traumatic brain injury (TBI). Inhibiting M1 and stimulating M2 activated microglia have demonstrated protective effects in several animal models of central nervous system diseases. However, it is not clear whether the polarization of microglia to M2 attenuates axonal injury following TBI. In this study, we used a lateral fluid percussion injury device to induce axonal injury in mice. Mice were randomly assigned to the sham, TBI, TBI + rosiglitazone (peroxisome proliferator-activated receptor gamma [PPAR-γ] agonist), and TBI + GW9662 (PPAR-γ antagonist) groups. Axonal injury was assessed using immunohistochemical staining for beta amyloid precursor protein. The inflammatory response was assessed by enzyme-linked immunosorbent assay, microglia polarization was assessed using specific markers of M1 and M2 microglia, and neurological function was assessed using the neurological severity score. Following TBI, microglia of the M1 phenotype increased significantly, while those of the M2 phenotype decreased. Rosiglitazone-induced PPAR-γ activation promoted microglia polarization to the M2 phenotype, which reduced the inflammatory response, attenuated axonal injury in the cerebral cortex, and improved neurological function. Conversely, GW9662 inhibited the polarization of microglia to M2 and aggravated inflammation and axonal injury. Our in vitro findings in lipopolysaccharide-induced microglia were consistent with those of our in vivo experiments. In conclusion, the polarization of microglia to the M2 phenotype via PPAR-γ activation attenuated axonal injury following TBI in mice, which may be a potential therapeutic approach for TBI-induced axonal injury.

Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

“…As a widely used antidiabetic drug which works as an insulin sensitizer by binding to the PPAR‐γ in fat cells, RSG may also serve as a master gatekeeper in CNS injury and repair . It is emerging that the PPAR‐γ is constitutively expressed in microglia and activating PPAR‐γ in microglia may regulate the phenotypic change of microglia . PPAR‐γ activation could favor a reprogramming process of microglia toward a beneficial phenotype, with anti‐inflammatory and tissue‐repair properties .…”

“…[37][38][39] It is emerging that the PPAR-γ is constitutively expressed in microglia and activating PPAR-γ in microglia may regulate the phenotypic change of microglia. [40][41][42][43] PPAR-γ activation could favor a reprogramming process of microglia toward a beneficial phenotype, with antiinflammatory and tissue-repair properties. [10][11][12][13]44 Interestingly, previous studies have shown that 1 day after ischemia, the microglia/macrophages adopt an anti-inflammatory phenotype that progressively evolves toward a neurotoxic phenotype at day 7 poststroke.…”

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Accordingly, HMGB1 is also reported to be an important mediator of inflammation in epilepsy models and has potential as a predictive biomarker of epileptic seizures . Rosiglitazone, a potent peroxisome proliferator‐activated receptor γ (PPARγ) agonist with anti‐inflammatory properties, has been reported to induce M2 polarization in a TBI model in mice, attenuating axonal injury and improving neurological function . However, improved TBI outcomes by rosiglitazone may also involve other biological mechanisms, such as limiting the mitochondrial dysfunction and oxidative damage, as well as suppressing autophagy .…”

“…10,84 Rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist with anti-inflammatory properties, has been reported to induce M2 polarization in a TBI model in mice, attenuating axonal injury and improving neurological function. 85 However, improved TBI outcomes by rosiglitazone may also involve other biological mechanisms, such as limiting the mitochondrial dysfunction and oxidative damage, as well as suppressing autophagy. 86,87 Previous studies also suggest that PPARγ agonists provide neuroprotection and suppress development of epileptic seizures in animal models of temporal lobe epilepsy.…”

Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

“…Peroxisome proliferator activated receptor gamma (PPAR-γ) plays an important role in regulating transcription expression of anti-inflammatory cytokines . Studies have shown that PPAR-γ agonists (pioglitazone or rosiglitazone) can switch the transition of microglia cells from a proinflammatory to an anti-inflammatory state , Wen et al, 2018. Natural compounds have broad prospects in neuroimmune regulation.…”