The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO−/− mice was accompanied by impaired recruitment of Ly6Chigh monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO−/− mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
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M.A.O., J.J.O., and J.L.C. were supported by Veterans Affairs Merit Grants 1I01BX000656, BX002120-01, and I01CX000911, respectively. B.B.M. was supported by National Institutes of Health Grants AI117229, HL127805, and HL119682. L.M.N. was supported by National Institutes of Health Research Training Grant T32 HL07749. A.J.E. was supported by National Institutes of Health Training Grant T32 AI007413.
Abbreviations used in this article:
- BMM and DC
- bone marrow–derived macrophage
- conventional DC
- dendritic cell
- day postinfection
- inducible NO synthase
- macrophage receptor with collagenous structure
- MHC class II
- monocyte-derived DC
- real-time quantitative PCR.
- Received January 11, 2017.
- Accepted February 21, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.