Bone Marrow-Derived Microglia Infiltrate into the Paraventricular Nucleus of Chronic Psychological Stress-Loaded Mice

Background: Microglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS) induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow. Methods and Findings: Here we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN) of mice that received chronic PS. Bone marrow derived-microglia are CX(3)CR1(low)CCR2(+)CXCR4(high), as distinct from CX(3)CR1(high)CCR2-CXCR4(low) resident microglia, and express higher levels of interleukin-1 beta (IL-1 beta) but lower levels of tumor necrosis factor-alpha (TNF-alpha). Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1) in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1) in the bone marrow and increases the frequency of CXCR4(+) monocytes in peripheral circulation. And then a chemokine (C-C motif) receptor 2 (CCR2) or a beta(3)-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN. Conclusion: Chronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.