Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration

Abstract

Traumatic brain injury (TBI) is one of the most common diseases in the central nervous system (CNS) with high mortality and morbidity. Patients with TBI usually suffer many sequelae in the life time post injury, including neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the pathological mechanisms connecting these two processes have not yet been fully elucidated. It is important to further investigate the pathophysiological mechanisms underlying TBI and TBI-induced neurodegeneration, which will promote the development of precise treatment target for these notorious neurodegenerative consequences after TBI. A growing body of evidence shows that neuroinflammation is a pivotal pathological process underlying chronic neurodegeneration following TBI. Microglia, as the immune cells in the CNS, play crucial roles in neuroinflammation and many other CNS diseases. Of interest, microglial activation and functional alteration has been proposed as key mediators in the evolution of chronic neurodegenerative pathology following TBI. Here, we review the updated studies involving phenotypical and functional alterations of microglia in neurodegeneration after injury, survey key molecules regulating the activities and functional responses of microglia in TBI pathology, and explore their potential implications to chronic neurodegeneration after injury. The work will give us a comprehensive understanding of mechanisms driving TBI-related neurodegeneration and offer novel ideas of developing corresponding prevention and treatment strategies for this disease.

Keywords: central nervous system; microglia; neurodegeneration; neuroinflammation; traumatic brain injury.

FIGURE 1

Heterogeneity of microglia: phenotypic and functional diversity. In response to disturbance of brain homeostasis like injury or disease, microglia can become polarized toward M1-like and M2-like activation states that can have distinct roles in neurodegeneration and tissue repair. An environment rich with the classical pro-inflammatory stimuli, such as IFN-γ and LPS, promotes the polarization of resting microglia into an M1 phenotype. M1-like microglia are characterized by upregulated expression of phenotypic protein markers such as IL-1β, TNFα, IL-6, and iNOS. They release pro-inflammatory cytokines, chemokines and free radicals that impair brain repair and contribute to chronic neuroinflammation, oxidative stress and long-term neurological impairments. In contrast, a neuroinflammatory environment rich in anti-inflammatory IL-4 or IL-13 drives the development of an M2 phenotype. M2-like microglia upregulate protein markers such as CD206, CD163, FCγR, arginase 1, Ym-1, and TGFβ. M2-like microglia release anti- inflammatory cytokines, neurotrophic factors and proteases, and they have increased phagocytic activity. M2-like microglia promote immunosuppression and resolution of M1-mediated neuroinflammation, and participate in CNS remodeling and repair by modulating neurorestorative processes such as neurogenesis, angiogenesis, oligodendrogenesis and remyelination.

FIGURE 2

Schematic diagram of microglia-mediated neuroinflammation signaling pathways after TBI. In response to TBI, DAMPs such as HMGB1 can promote priming of the NLRP3 inflammasome through NF-κB signaling. In microglia, activation of P2X7 receptor could stimulate the NLRP3 inflammasome, which subsequently leads to the outflow of pro-inflammatory cytokines including IL-18 and IL-1β. CX3CL1 is also known to induce microglia activation through intracellular phosphorylation of microglial p38 MAPK. Further, treatment of cultured microglia with CX3CL1 promoted cell survival and inhibited Fas ligand-induced cell death via the Akt signaling pathway. TLR signaling initiates acute inflammatory response by promoting the release of pro-inflammatory cytokines. Ligand binding to TLR4 activates either a MyD88-dependent NF-κB activation or MyD88-independent activation of interferon regulatory factor-3 (IRF-3) activation and the subsequent expression of IFNβ. The TREM2 pathway is responsible for switching from a homeostatic to a neurodegenerative microglial phenotype after phagocytosis of apoptotic neurons. Upon activation, the PPARs regulate inflammation via trans-reexpression of multiple inflammatory signaling systems such as NFκB, activator protein-1 (AP-1), signal transducer and activator of transcription (STAT) to result in M1/M2 microglia polarization and facilitate it toward an anti-inflammatory state. In LPS induced neuroinflammation, LRRK2 could phosphorylate p53 and promote the production of pro-inflammatory cytokine such as tumor necrosis factor (TNF)-α. Activation of NOX2 aggravated inflammatory-mediated neurodegeneration after TBI via inhibiting switch from M1-like activation to M2- like activation of microglia. Pro-inflammatory cytokines expressed by microglia, including interferon-γ, interleukin-1β, and tumor necrosis factor-α, can specifically stimulate Aβ accumulation while anti-inflammatory cytokines such as IL-1ra, IL-10, and TGF preclude formation of Aβ. HMGB1, high mobility group box 1; N-FκB, nuclear factor-kappa B; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; IFN-β, IRF-3-inducing interferon-b. TREM2, triggering receptor expressed on myeloid cells 2. LRRK2, leucine-rich repeat kinase 2; LPS, lipopolysaccharide; PPARγ, peroxisome proliferator-activated receptor gamma. IL-1ra, interleukin-1 receptor antagonist; Aβ, beta amyloid.