To investigate microglial mechanisms in central and peripheral inflammation after experimental traumatic brain injury (TBI), we inhibited the colony-stimulating factor-1 receptor (CSF-1R) with PLX5622 (PLX). We hypothesized that microglia depletion would attenuate central inflammation acutely with no effect on peripheral inflammation. After randomization, male mice (n = 105) were fed PLX or control diets (21 days) and then received midline fluid percussion injury or sham injury. Brain and blood were collected at 1, 3, or 7 days post-injury (DPI). Immune cell populations were quantified in the brain and blood by flow cytometry. Cytokines (interleukin [IL]-6, IL-1β, tumor necrosis factor-α, interferon-γ, IL-17A, and IL-10) were quantified in the blood using a multi-plex enzyme-linked immunosorbent assay. Data were analyzed using Bayesian multi-variate, multi-level models. PLX depleted microglia at all time points and reduced neutrophils in the brain at 7 DPI. PLX also depleted CD115⁺ monocytes, reduced myeloid cells, neutrophils, and Ly6C^low monocytes in blood, and elevated IL-6. TBI induced a central and peripheral immune response. TBI elevated leukocytes, microglia, and macrophages in the brain and elevated peripheral myeloid cells, neutrophils, Ly6C^int monocytes, and IL-1β in the blood. TBI lowered peripheral CD115⁺ and Ly6C^low monocytes in the blood. TBI PLX mice had fewer leukocytes and microglia in the brain at 1 DPI, with elevated neutrophils at 7 DPI compared to TBI mice on a control diet. TBI PLX mice also had fewer peripheral myeloid cells, CD115⁺, and Ly6C^low monocytes in the blood at 3 DPI, but elevated Ly6C^high, Ly6C^int, and CD115⁺ monocyte populations at 7 DPI, compared to TBI mice on a control diet. TBI PLX mice had elevated proinflammatory cytokines and lower anti-inflammatory cytokines in the blood at 7 DPI compared to TBI mice on a control diet. CSF-1R inhibition reduced the immune response to TBI at 1 and 3 DPI, but elevated peripheral inflammation at 7 DPI.

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