Chemokine CCL18 Promotes Phagocytosis Through Its Receptor CCR8 Rather than PITPNM3 in Human Microglial Cells

CCL18 is a CC chemokine that exhibits diverse functions through interaction with various cell subsets with both proinflammatory anti-inflammatory properties through its receptors CCR8 (CC Chemokine Receptor 8) and PITPNM3 (phosphatidylinositol transfer protein 3). However, the function of CCL18 in microglia remains unclear. In this study, we show that CCL18 did not change the expression of the inflammatory factors, interleukin (IL)-1β, IL-6, tumor necrosis factor Alpha (TNF-α), or inducible nitric oxide synthase (iNOS), but significantly induced expression of the macrophage markers, MRC-1 and ARG-1 M2, in a human microglial clone 3 cell line (HMC3). Phagocytosis by HMC3 cells was significantly enhanced in the presence of CCL18, indicated by uptake of Amyloid-β and dextran. CCR8 and PITPNM3 were both expressed on HMC3 cells, but selective knockdown of CCR8 and PITPNM3 showed that only the former played a dominant role in phagocytosis of HMC3 through the nuclear factor kappa B (NF-κB)/Src signaling pathway. Our results suggest that CCL18 could have anti-inflammatory activity and activate the phagocytic function of microglia, which is involved in neural development, homeostasis, and repair mechanisms.