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

Chinaemerem U. Onyishi, Guillaume E. Desanti, Alex L. Wilkinson, Samuel Lara-Reyna, Eva-Maria Frickel, Gyorgy Fejer, Olivier D. Christophe, Clare E. Bryant, Subhankar Mukhopadhyay, Siamon Gordon and Robin C. May ()
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Chinaemerem U. Onyishi: University of Birmingham, Edgbaston
Guillaume E. Desanti: University of Birmingham, Edgbaston
Alex L. Wilkinson: University of Birmingham, Edgbaston
Samuel Lara-Reyna: University of Birmingham, Edgbaston
Eva-Maria Frickel: University of Birmingham, Edgbaston
Gyorgy Fejer: University of Plymouth
Olivier D. Christophe: Université Paris-Saclay, INSERM, Hémostase inflammation thrombose HITH U1176
Clare E. Bryant: University of Cambridge, Department of Medicine, Box 157, Level 5, Addenbrooke’s Hospital, Hills Road
Subhankar Mukhopadhyay: King’s College London
Siamon Gordon: Chang Gung University
Robin C. May: University of Birmingham, Edgbaston

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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 FcγR 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.

Date: 2023
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DOI: 10.1038/s41467-023-40635-w

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