Serial systemic injections of endotoxin (LPS) elicit neuroprotective spinal cord microglia through IL-1-dependent cross-talk with endothelial cells.

Microglia are dynamic immunosurveillance cells in the CNS. Whether microglia are protective or pathological is context-dependent; the outcome varies as a function of time relative to the stimulus, activation state of neighboring cells in the microenvironment or within progression of a particular disease. Although brain microglia can be 'primed' using bacterial lipopolysaccharide/endotoxin (LPS), it is unknown whether LPS delivered systemically can also induce neuroprotective microglia in the spinal cord. Here, we show that serial systemic injections of LPS (1 mg/kg daily; i.p.) for four consecutive days (LPSx4) consistently elicit a reactive spinal cord microglia response marked by dramatic morphological changes, increased production of IL-1, and enhanced proliferation without triggering leukocyte recruitment or overt neuropathology. Following LPSx4, reactive microglia frequently contact spinal cord endothelial cells. Targeted ablation or selective expression of IL-1 and IL-1R in either microglia or endothelia reveal that IL-1 dependent signaling between these cells mediates microglia activation. Using a mouse model of ischemic spinal cord injury (ISCI) in male and female mice, we show that pre-operative LPSx4 provides complete protection from ischemia-induced neuron loss and hindlimb paralysis. Neuroprotection is partly reversed by either pharmacological elimination of microglia or selective removal of IL-1R in microglia or endothelia. These data indicate that spinal cord microglia are amenable to therapeutic reprogramming via systemic manipulation and that this potential can be harnessed to protect the spinal cord from injury.SIGNIFICANCE STATEMENTData in this report indicate that a neuroprotective spinal cord microglia response can be triggered by daily systemic injections of LPS over a period four days (LPSx4). The LPSx4 regimen induces morphological transformation and enhances proliferation of spinal cord microglia without causing neuropathology. Using advanced transgenic mouse technology, we show that IL-1-dependent microglia-endothelial cross talk is necessary for eliciting this spinal cord microglia phenotype and also for conferring optimal protection to spinal motor neurons from ischemic spinal cord injury (ISCI). Collectively, these novel data show that it is possible to consistently elicit spinal cord microglia via systemic delivery of inflammogens to achieve a therapeutically effective neuroprotective response against ISCI.