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

Author

Listed:
  • 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
    University of Oxford)

  • Robin C. May

    (University of Birmingham, Edgbaston)

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.

Suggested Citation

  • 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 Gor, 2023. "Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40635-w
    DOI: 10.1038/s41467-023-40635-w
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