Microglial repopulation resolves inflammation and promotes brain recovery after injury

Abstract

Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as well as elevated levels of cytokines, chemokines, complement, and other inflammatory signals. These collective responses are largely resolved by microglial repopulation. Furthermore, microglial repopulation promotes functional recovery in mice, with elevated plus maze performance matching that of uninjured mice, despite the loss of 80% of hippocampal neurons. Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation, suggesting that these cells sculpt and regulate the synaptic landscape. Thus, our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.

Traumatic brain injury‐induced neuronal damage in the somatosensory cortex causes formation of rod‐shaped microglia that promote astrogliosis and persistent neuroinflammation

“…As we and others have reported, PLX5622 administration robustly reduced the presence of Iba1 + microglia (Figure b) (McKim et al, ; Rice et al, ; Rice et al, ). Indeed, 21 day administration of PLX5622 resulted in an ~97% reduction of the number of Iba1 + microglia compared to vehicle‐fed controls (Figure c, F 1,10 = 271.233; p < .001).…”

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

“…We identified several orally bioavailable CSF1R inhibitors that noninvasively cross the blood‐brain barrier, leading to brain‐wide microglial elimination within days, which continues for as long as CSF1R inhibition is present (Dagher et al, 2015; Elmore et al, 2014). In particular, removal of CSF1R inhibition stimulates the rapid repopulation of the entire brain with new microglial cells (Elmore et al, 2014; Elmore, Lee, West, & Green, 2015; Rice et al, 2017), effectively replacing the entire microglial tissue. This process takes approximately 14–21 days to complete; thereafter, the new microglia are virtually indistinguishable (i.e., cell densities, morphologies, and gene expression profiles) from the resident microglial tissue.…”

“…We have shown that CSF1R inhibitor‐dependent microglial replacement essentially “resets” this “reactive” microglial population, whereby returning microglia resemble nonreactive homeostatic microglia and promote functional recovery (Rice et al, 2017). Thus, microglial elimination and repopulation may be beneficial in situations that implicate altered microglial phenotypes in impaired brain function.…”

Sexual dimorphism in the inflammatory response to traumatic brain injury

“…These inflammatory responses are a classic component of the secondary injury cascade and are associated with neuronal death (Corps et al 2015). This neuroinflammation begins in the acute phase but can last for years post-injury in both humans and animals (Johnson et al 2013; Kumar et al 2013; Rice et al 2017; Smith et al 2013). Microglial/macrophages (MG/Mϕ) are the main players in propagating inflammation to tissues neighboring the core site of injury.…”