There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as ‘neuroinflammatory’. Aspects of neuroinflammation vary within the context of disease, injury, infection, or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical, and behavioral consequences. Microglia, innate immune cells of the CNS, play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context‐specific manner and detail both positive and negative aspects of neuroinflammatory processes. image In this review, we will use brain and spinal cord injury, stress, aging, and other inflammatory events to illustrate the potential harm and benefits inherent to neuroinflammation. Context, course, and duration of the inflammation are highly important to the interpretation of these events, and we aim to provide insight into this by detailing several commonly studied insults.This article is part of the 60th anniversary supplemental issue.

Social stress is associated with altered immunity and higher incidence of anxiety-related disorders. Repeated social defeat (RSD) is a murine stressor that primes peripheral myeloid cells, activates microglia, and induces anxiety-like behavior. Here we show that RSD-induced anxiety-like behavior corresponded with an exposure-dependent increase in circulating monocytes (CD11b⁺/SSC^lo/Ly6C^hi) and brain macrophages (CD11b⁺/SSC^lo/CD45^hi). Moreover, RSD-induced anxiety-like behavior corresponded with brain region-dependent cytokine and chemokine responses involved with myeloid cell recruitment. Next, LysM-GFP⁺and GFP⁺bone marrow (BM)-chimeric mice were used to determine the neuroanatomical distribution of peripheral myeloid cells recruited to the brain during RSD. LysM-GFP⁺mice showed that RSD increased recruitment of GFP⁺macrophages to the brain and increased their presence within the perivascular space (PVS). In addition, RSD promoted recruitment of GFP⁺macrophages into the PVS and parenchyma of the prefrontal cortex, amygdala, and hippocampus of GFP⁺BM-chimeric mice. Furthermore, mice deficient in chemokine receptors associated with monocyte trafficking [chemokine receptor-2 knockout (CCR2^KO) or fractalkine receptor knockout (CX₃CR1^KO)] failed to recruit macrophages to the brain and did not develop anxiety-like behavior following RSD. Last, RSD-induced macrophage trafficking was prevented in BM-chimeric mice generated with CCR2^KOor CX₃CR1^KOdonor cells. These findings indicate that monocyte recruitment to the brain in response to social stress represents a novel cellular mechanism that contributes to the development of anxiety.

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), and chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion injury (FPI) in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To understand the relationship between microglia, neurons, and other glia, single-cell RNA sequencing was completed 7 dpi, a critical time point in the evolution from acute to chronic pathogenesis. Cortical microglia exhibited distinct TBI-associated clustering with increased type-1 interferon and neurodegenerative/damage-related genes. In cortical neurons, genes associated with dopamine signaling, long-term potentiation, calcium signaling, and synaptogenesis were suppressed. Microglial depletion reversed the majority of these neuronal alterations. Furthermore, there was reduced cortical dendritic complexity 7 dpi, reduced neuronal connectively 30 dpi, and cognitive impairment 30 dpi. All of these TBI-associated functional and behavioral impairments were prevented by microglial depletion. Collectively, these studies indicate that microglia promote persistent neuropathology and long-term functional impairments in neuronal homeostasis after TBI.SIGNIFICANCE STATEMENTMillions of traumatic brain injuries (TBIs) occur in the United States alone each year. Survivors face elevated rates of cognitive and psychiatric complications long after the inciting injury. Recent studies of human brain injury link chronic neuroinflammation to adverse neurologic outcomes, suggesting that evolving inflammatory processes may be an opportunity for intervention. Here, we eliminate microglia to compare the effects of diffuse TBI on neurons in the presence and absence of microglia and microglia-mediated inflammation. In the absence of microglia, neurons do not undergo TBI-induced changes in gene transcription or structure. Microglial elimination prevented TBI-induced cognitive changes 30 d postinjury (dpi). Therefore, microglia have a critical role in disrupting neuronal homeostasis after TBI, particularly at subacute and chronic timepoints.