Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization

Abstract

Inflammation is an important mediator of secondary neurological injury after traumatic brain injury (TBI). Endocannabinoids, endogenously produced arachidonate based lipids, have recently emerged as powerful anti-inflammatory compounds, yet the molecular and cellular mechanisms underlying these effects are poorly defined. Endocannabinoids are physiological ligands for two known cannabinoid receptors, CB1R and CB2R. In the present study, we hypothesized that selective activation of CB2R attenuates neuroinflammation and reduces neurovascular injury after TBI. Using a murine controlled cortical impact (CCI) model of TBI, we observed a dramatic upregulation of CB2R within infiltrating myeloid cells beginning at 72 h. Administration of the selective CB2R agonist, GP1a (1-5 mg/kg), attenuated pro-inflammatory M1 macrophage polarization, increased anti-inflammatory M2 polarization, reduced edema development, enhanced cerebral blood flow, and improved neurobehavioral outcomes after TBI. In contrast, the CB2R antagonist, AM630, worsened outcomes. Taken together, our findings support the development of selective CB2R agonists as a therapeutic strategy to improve TBI outcomes while avoiding the psychoactive effects of CB1R activation.

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

“…However, whether microglial modulation is dependent on eCB has not been examined. In a recent study, CB2R agonist GP1a was examined in a TBI model induced by CCI (111). TBI-induced edema, anxiety, and motor dysfunction were ameliorated at 3 mg/kg of GP1a and to a lesser degree at 5 mg/kg.…”

“…When fluorescence-labeled macrophages were administered intravenously, CB2R immunoreactivity after TBI was correlated with increased fluorescence; this correlation suggests that the cells expressing CB2R in the CNS are mainly macrophages. Based on these observations, it was postulated that mainly the infiltrated macrophages are responsible for the increase in M2 marker expression by CB2 activation; however, the contribution of microglia cannot be dismissed (111).…”

Bone marrow derived extracellular vesicles activate osteoclast differentiation in traumatic brain injury induced bone loss

“…In particular, bone resorption and differentiation of osteoclast precursors to mature cells is regulated by the pro-inflammatory transcription factors, NFB, and RANKL [40,41]. Of note, we reported increased chronic inflammatory activation, involving the mobilization of bone marrow derived immune cells, within both blood and brain following a TBI [25,[33][34][35][36]. Consistent with these findings, the key NFB genes, RelA/p65 and Birc3, were dysregulated in the bone marrow Taken together, our study raises the interesting possibility that TBI fosters a chronic proinflammatory state within the bone marrow niche, culminating in increased bone resorption.…”

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

“…In one study delivering recombinant IL-4 after stroke in IL-4 knockout mice, repeated measures were not accounted for and wild-type mice were not tested (52). A variety of other approaches to TBI that promote an M2-like response have also observed improvement in behavioral outcomes (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (31)(32)(33)(34)(35)(36). However, in many of these studies, behavior is not (or could not be) assessed prior to treatment to ensure the absence of accidental bias.…”