Reciprocal regulation of TLR4, TLR3 and Macrophage Scavenger Receptor 1 regulates nonopsonic phagocytosis of the fungal pathogenCryptococcus neoformans

Abstract

AbstractThe opportunistic fungal pathogenCryptococcus neoformanscauses lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear howC. neoformansis recognized and phagocytosed by macrophages. Here we investigate the role of TLR4 in the nonopsonic phagocytosis ofC. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of nonopsonized cryptococci. The increased phagocytosis observed inTlr4-/-cells was dampened by pre-treatment of macrophages with either a TLR3 inhibitor or oxidised-LDL, a known ligand of scavenger receptors. The scavenger receptor, macrophage scavenger receptor 1 (MSR1) (also known as SR-A1 or CD204) was upregulated inTlr4-/-macrophages and there was a 75% decrease in phagocytosis of nonopsonized cryptococci byMsr1-/-macrophages. Furthermore, immunofluorescence imaging revealed colocalization of MSR1 and internalised cryptococci. Together, these results identify MSR1 as a key receptor for the phagocytosis of nonopsonizedC. neoformansand demonstrate TLR4/MSR1 crosstalk in the phagocytosis ofC. neoformans.