Immune Activation Promotes Depression 1 Month After Diffuse Brain Injury: A Role for Primed Microglia

Abstract

Background Traumatic brain injury (TBI) is associated with a higher incidence of depression. The majority of individuals who suffer a TBI are juveniles and young adults and thus, the risk of a lifetime of depressive complications is a significant concern. The etiology of increased TBI-associated depression is unclear, but may be inflammatory-related with increased brain sensitivity to secondary inflammatory challenges (e.g., stressors, infection, and injury). Methods Adult male BALB/c mice received a sham (n=52) or midline fluid percussion injury (TBI) (n=57). Neuroinflammation, motor coordination (rotarod), and depressive behaviors (social withdrawal, immobility in the tail suspension test, and anhedonia) were assessed 4 h, 24 h, 72 h, 7 d, or 30 d later. Moreover, 30 d after surgery, sham and TBI mice received a peripheral injection of saline or lipopolysaccharide (LPS) and microglia activation and behavior were determined. Results Diffuse TBI caused inflammation, peripheral cell recruitment, and microglia activation immediately after injury coinciding with motor coordination deficits. These transient events resolved within 7 d. Nonetheless, 30 days post-TBI a population of de-ramified and major histocompatibility complex (MHC)II+ (primed) microglia were detected. After a peripheral LPS challenge, the inflammatory cytokine response in primed microglia of TBI mice was exaggerated compared to microglia of controls. Furthermore, this LPS-induced microglia reactivity 30 d after TBI was associated with the onset of depressive-like behavior. Conclusions These results implicate a primed and immune-reactive microglial population as a possible triggering mechanism for the development of depressive complications after TBI.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…For instance, aged rodents demonstrate increased expression of mRNA and protein markers of inflammation following LPS challenge (Kumar et al, 2013;Norden and Godbout, 2013;Norden et al, 2015aNorden et al, , 2015b. In addition to aging, similar priming effects have been reported in microglia from patients with neuropsychiatric disorders including traumatic brain injury (Fenn et al, 2014) and neurodegeneration (Norden et al, 2015a). Of note, primed microglia were less responsive to the effects of glutamate reuptake enhancing agent riluzole compared with unprimed microglia from younger individuals (Brothers al, 2013).…”

“…Once established in the brain parenchyma, microglial cell lines are sustained by the proliferation of resident microglial progenitor cells. Microglial activity and its morphology is highly contextsensitive and depends on the spatial and temporal distribution of the physiological or pathogenic influences (Fenn et al, 2014;Figuera-Losada et al, 2014;Kettenmann and Ransom, 2012;Reus et al, 2015;Torres-Platas et al, 2014a; TorresPlatas et al, 2014b). However, defining and staging microglial activation states have been complicated by the lack of unbiased insights into the contextual factors driving authentic microglial reaction states (Ransohoff, 2016).…”

“…Recent evidence suggests that activated microglia can reside in an in-between state of partial activation known as priming characterized both by increased responsivity to immune stimulation and persistent, chronic elevations of baseline cytokine secretion during unstimulated conditions (Dilger and Johnson, 2008;Godbout and Johnson, 2009;Godbout et al, 2008). This phenomenon of priming requires both a priming stimulus (such as chronic activation by IFN-γ) and a secondary but acute triggering stimulus such as TLR binding by bacterial antitoxins (Eggen et al, 2013;Fenn et al, 2014). The priming stimulus appears to cause a phenotypic shift towards a more sensitized state characterized by the increased expression of MHC class II and increased glutamate release.…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…52 Microglia isolated from mice that had been injected peripherally with LPS 1 month after TBI showed increased IL-1β and TNF-α mRNA expression relative to microglia from LPS exposed only mice. 53 This heightened microglial activity was accompanied by depressivelike behaviors in the mice. Although suggestive, this is not direct evidence for DAMP-induced microglial training however, as TBI is a complex multifaceted phenomenon and the microglia were not stimulated ex vivo, thus raising the possibility that interactions with other cell types may have been responsible for the upregulation of microglial proinflammatory function.…”

“…In animal models, for example, the combination of prenatal polyI:C (which activates TLR-3 (ref. 68)) followed by peripubertal stress, 69 or TBI followed by LPS, 53 induce depressive-like behaviors. These findings cannot be easily explained by adaptive immunity or classical understandings of innate immunity.…”