Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen

The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognised and phagocytosed by macrophages. Here we investigate the role of TLR4 in the non-opsonic phagocytosis of C. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of non-opsonised cryptococci by murine and human macrophages. The increased phagocytosis observed in Tlr4(-/-) cells was dampened by pre-treatment of macrophages with 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 in Tlr4(-/-) macrophages. Genetic ablation of MSR1 resulted in a 75% decrease in phagocytosis of non-opsonised cryptococci, strongly suggesting that it is a key non-opsonic receptor for this pathogen. We go on to show that MSR1-mediated uptake likely involves the formation of a multimolecular signalling complex involving Fc & gamma;R leading to SYK, PI3K, p38 and ERK1/2 activation to drive actin remodelling and phagocytosis. Altogether, our data indicate a hitherto unidentified role for TLR4/MSR1 crosstalk in the non-opsonic phagocytosis of C. neoformans. Fungal pathogens are recognised and phagocytosed by macrophages in the early stages of infection. Here, Onyishi et al. identify a crosstalk between Toll Like Receptor 4 and Macrophage Scavenger Receptor 1 in the regulation of Cryptococcus neoformans uptake.

Automated summary

Loss of TLR4 function enhances phagocytosis of non-opsonised C. neoformans by macrophages, and this is dampened by pre-treatment with oxidised-LDL. The scavenger receptor MSR1 is upregulated in Tlr4(-/-) macrophages and is shown to be a key non-opsonic receptor for C. neoformans.