Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40635-w |
| _version_ | 1797558038880583680 |
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| author | 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 Robin C. May |
| author_facet | 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 Robin C. May |
| author_sort | Chinaemerem U. Onyishi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:24:47Z |
| format | Article |
| id | doaj.art-d574524e28824efda336edb4bafa128e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:24:47Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d574524e28824efda336edb4bafa128e2023-11-20T10:14:07ZengNature PortfolioNature Communications2041-17232023-08-0114111310.1038/s41467-023-40635-wToll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogenChinaemerem U. Onyishi0Guillaume E. Desanti1Alex L. Wilkinson2Samuel Lara-Reyna3Eva-Maria Frickel4Gyorgy Fejer5Olivier D. Christophe6Clare E. Bryant7Subhankar Mukhopadhyay8Siamon Gordon9Robin C. May10Institute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonInstitute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonInstitute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonInstitute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonInstitute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonSchool of Biomedical Sciences, Faculty of Health, University of PlymouthUniversité Paris-Saclay, INSERM, Hémostase inflammation thrombose HITH U1176University of Cambridge, Department of Medicine, Box 157, Level 5, Addenbrooke’s Hospital, Hills RoadPeter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College LondonDepartment of Microbiology and Immunology, College of Medicine, Chang Gung UniversityInstitute of Microbiology & Infection and School of Biosciences, University of Birmingham, EdgbastonAbstract 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.https://doi.org/10.1038/s41467-023-40635-w |
| spellingShingle | 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 Robin C. May Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen Nature Communications |
| title | Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| title_full | Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| title_fullStr | Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| title_full_unstemmed | Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| title_short | Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| title_sort | toll like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen |
| url | https://doi.org/10.1038/s41467-023-40635-w |
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