Beyond microglia: Peripheral immune cells in the developing rat brain

Microglia have long been thought to be responsible for the initiation of the central nervous system (CNS) immune response to pathogen exposure. However, we recently reported that depleting CNS microglia and circulating monocytes does not abrogate the sickness response in male rats or mice to bacterial endotoxin, lipopolysaccharide (LPS). How the central immune response to an endotoxin challenge is initiated and resolved in the absence of microglia and monocytes remains unclear. Here we investigated the role of microglia and monocytes in driving the behavioral, febrile and neuroimmune response to LPS using the Cx3cr1-Dtr rat model of conditional microglia/monocyte depletion, assessed if this role is similar in females and males, and examined how the response to an immune challenge might be initiated in the absence of these cells. We show that depletion of microglia and monocytes exacerbates the response to LPS at each phase of the immune cascade. Our data indicate that the changes in the central response to immune challenge may be an indirect effect of excess neutrophil expansion into the bloodstream and infiltration into peripheral organs stimulating a rapid and exacerbated cytokine and prostaglandin response to the LPS that is not curtailed by the usual negative feedback mechanisms. Thus, we show that a demonstrable immune response can be generated (and resolved) in the near complete absence of microglia and monocytes and that these cells play a regulatory role in the initiation and resolution of the response to an immune challenge, rather than being critical for it to occur.