Effects of CX3CR1 or CCR2 deficiency on circulating immune cell infiltration, microglia activation and neurophysiological property in white matter tract following endotoxemia

Abstract

Abstract Background Brain white matter (WM) malfunction is deeply involved in many neurological and psychiatric disorders, and may lead to problems with cognition. Neuroinflammation occurs in the majority of WM injuries regardless of pathogenesis. Adverse effects of neuroinflammation on neurophysiological properties of the WM tracts has been observed before. The fractalkine (CX3CL1) and monocyte chemoattractant protein-1 (CCL2) and their respective receptors, CX3CR1 and CCR2, play important roles in immune cell infiltration and microglia activation. Whether the CX3CL1 or CCL2 and their receptors associated neuroinflammation would change neurophysiological property of the WM tract remains unknown. Methods In this work, we used a common leukocyte marker CD45 to explore the extent to which the circulating immune cells were recruited into the corpus callosum (CC) WM, and the CC microglia were activated, reflected by proportional area, in the CCR2+/+CX3CR1−/− or CX3CR1+/+CCR2−/− mouse following systemic lipopolysaccharide (LPS). Then, electrophysiological recording of WM tract compound action potentials (CAP) was performed in normal and LPS treated CCR2+/+CX3CR1−/− or CX3CR1+/+CCR2−/− mouse. Results 1) Nearly significant more infiltrated circulating immune cells were found in the CC of CX3CR1+/+CCR2−/− mouse following systemic LPS. 2) Significant larger microglial proportional area was identified, after endotoxemia, in the CC of CX3CR1+/+CCR2−/− mouse, comparing to that in the CCR2+/+CX3CR1−/− mouse. 3) Absence of either CX3CR1 or CCR2 reduced the density of microglia in the normal CC WM. 4) Endotoxemia induced a nearly significant downshift of N1 (myelinated axon) input-output curve, and a slight downshift of N2 (unmyelinated axon) input-output curve recorded from the CC of CX3CR1+/+CCR2−/− mouse, which was not detected in the CCR2+/+ CX3CR1−/− mouse. Conclusions CX3CR1 plays more significant roles in guiding infiltration of circulating immune cells into the CC WM, and in activation of CC microglia following systemic LPS. Consequently, CX3CR1 mediated inflammation evidently declines the WM tract conductivity during endotoxemia. A possibility that endotoxin-mediated microglial pseudopodia distortion may impact WM tract signal transmission was discussed, as we had demonstrated microglial pseudopodia directly contact with Ranvier’s node and paranodal segment. We thought inflammation-mediated declination of WM tract conductivity may interrupt brain network connectivity and lead to cognitive problems.