Microglial Activation as a Compelling Target for Treating Acute Traumatic Brain Injury

TLDR: By using rodent models of TBI, therapeutic evaluation studies reveal that several agents or strategies attenuate contused brain volume and neurological deficits by inhibiting microglia activation I but inducing microglial activation II, and future studies should focus on multiple therapeutic agents and strategies for optimal TBI therapy.

Abstract: Microglia and several inflammatory cytokines and neurotrophic growth factors are involved in traumatic brain injury (TBI). Tumor necrosis factor-alpha (TNF-α) can be released by microglia, astrocytes, and neurons. TNF-α has been reported to be both proneurogenic and antineurogenic, depending upon the model, method, and cell-derived region. There are two subtypes of microglia: M1 and M2. The former (or M1 subtype of non-phagocytic microglia) is able to secrete higher levels of TNF-α but lower levels of interleukin (IL)-10 (IL-10), an anti-inflammatory cytokine. Both the proinflammatory and the pro-apoptotic function can also be promoted by activation of tumor necrosis factor-receptor 1 (TNF-R1). In contrast, M2 activation produces lower levels of TNF-α but higher levels of IL-10. Pro-growth and survival pathways can be promoted by the activation of TNFR2. During the acute stage of TBI, both M1 subtype of microglia and TNF-R1 are activated to cause higher levels of TNF-α but lower levels of IL-10, which lead to suppressed neurogenesis, neuronal loss and organ dysfunction (so-called microglial activation I). In contrast, activation of both M2 subtype of microglia and TNF-R2 is able to promote neurogenesis and tissue recovery (so-called microglial activation II). The severity of TBI depends upon the net effects between microglial activation I and microglial activation II. Indeed, by using rodent models of TBI, therapeutic evaluation studies reveal that several agents or strategies attenuate contused brain volume and neurological deficits by inhibiting microglial activation I but inducing microglial activation II. For example, etanercept therapy might attenuate contused brain volume and neurological deficits by inactivating the M1 subtype and TNF-R1 to reduce the microglial activation I response, but it might promote neurogenesis and functional recovery by activating the M2 subtype and TNF-R2. Therefore, based on microglial responses I and II, we conclude that future studies should focus on multiple therapeutic agents and strategies for optimal TBI therapy.