Sex differences in glia reactivity after cortical brain injury

Abstract

Several brain disorders associated with neuroinflammation show sex differences in their incidence, onset, progression and/or outcome. The different regulation of the neuroinflammatory response in males and females could underlie these sex differences. In this study, we have explored whether reactive gliosis after a penetrating cortical injury exhibits sex differences. Males presented a higher density of Iba1 immunoreactive cells in the proximity of the wound (0–220 μm) than females. This sex difference was due to a higher number of Iba1 immunoreactive cells with nonreactive morphology. In addition microglia/macrophages in that region expressed arginase‐1, marker of alternatively activated microglia, and the neuroprotective protein Neuroglobin, in a greater proportion in males than in females. No sex differences were found in the number of astrocytes around the lesion. However, the percentage of astrocytes expressing chemokine (C‐C motif) ligand 2 (CCL2), involved in recruitment of immune cells and gliosis regulation, was higher in males. Males also presented a significantly higher density of neurons in the lesion edge than females. These findings indicate that male and female mice have different neuroinflammatory responses after a cortical stab wound injury and suggest that sex differences in reactive gliosis may contribute to sex differences in neuroinflammatory diseases. GLIA 2015;63:1966–1981

Microglial Function across the Spectrum of Age and Gender

“…Purinergic receptors are generally associated with microglial activation, and loss of this signaling can disrupt the transition from a quiescent to an inflammatory phenotype [90]. These differences are also recapitulated in injury models, as cortical lesion sites are predominated by either resting or anti-inflammatory microglia in males, while the opposite is the case for females [91]. Taken together, it is suggested by these data that the neuroimmune milieu in females is more inflammatory than males in both the healthy and injured states.…”

(Putative) sex differences in neuroimmune modulation of memory

“…In the brain, differential microglial migration and immune-related gene expression in males and females (Schwarz et al, 2012) emerge early in development. Differences in neuroimmune cells persist throughout the lifespan, with sex-dependent activation of astrocytes (Santos-Galindo et al, 2011; Acaz-Fonseca et al, 2015), microglia (Crain et al, 2013), and cytokine release (Speirs & Tronson, in review ) in response to immune challenge. Individual cytokines have sex-specific functions in the brain.…”

“…Sex differences in neuroimmune function span across cell types and cytokine responses (Santos-Galindo et al, 2011; Crain et al, 2013; Acaz-Fonseca et al, 2015), through development into adulthood (Schwarz et al, 2012; Tay et al, 2016), and from physiological responses to cognitive and affective processes (Lipton and Ticknor, 1979; Tonelli et al, 2008). These observations strongly implicate the neuroimmune system as a critical mediator of neural functions.…”

“…First, astrocytes are sex-dependently activated as a consequence of ischemia (Chisholm and Sohrabji, 2016). Second, the release of cytokines by astrocytes differs markedly in males and females (Santos-Galindo et al, 2011; Loram et al, 2012; Acaz-Fonseca et al, 2015). Together these demonstrate suggest that sex differences in cytokines after immune challenge are mediated, in part, by astrocyte activation.…”

“…The task is made more difficult by the lack of studies that directly compare males and females (Table 1; Hoogland et al, 2015). Indeed, when males and females are directly compared, it becomes clear that different patterns of cytokines are triggered by an immune challenge (Speirs & Tronson, in review ), and these differences are mediated in part by differential activation of astrocytes (Santos-Galindo et al, 2011; Acaz-Fonseca et al, 2015) and microglia (Schwarz et al, 2012; Bodhankar et al, 2015). The intricacies of neuroimmune signaling, together with the presence of sex differences at every level of analysis, suggests that the role of this system in plasticity is very different in males and females.…”