TY - JOUR
T1 - CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment
AU - Drummond, Rebecca A.
AU - Swamydas, Muthulekha
AU - Oikonomou, Vasileios
AU - Zhai, Bing
AU - Dambuza, Ivy
AU - Schaefer, Brian C.
AU - Bohrer, Andrea C.
AU - Mayer-Barber, Katrin D.
AU - Lira, Sergio A.
AU - Iwakura, Yoichiro
AU - Filler, Scott G.
AU - Brown, Gordon D.
AU - Hube, Bernhard
AU - Naglik, Julian R.
AU - Hohl, Tobias M.
AU - Lionakis, Michail S.
N1 - This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, as well as NIH grants awarded to TMH (R01 093808), SGF (R01AI124566) and SRL (R01CA161373). Additional funding was provided by the Burroughs Wellcome Fund (awarded to TMH), the Wellcome Trust (102705, 097377; awarded to GDB), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1; awarded to GDB). The authors additionally thank Celeste Huaman for care and screening of the Malt1 793 -/- mice.
PY - 2019/5
Y1 - 2019/5
N2 - The C-type lectin receptor/Syk adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human CARD9-deficiency causes fungal-specific CNS-targeted infection susceptibility. We previously showed that CARD9 is required for neutrophil recruitment to the fungal-infected CNS, which mediates fungal clearance. Here, we investigated host and pathogen factors that promote protective neutrophil recruitment during Candida albicans CNS invasion and examined their dependence on CARD9 for in vivo induction. We show that IL-1b is essential for CNS antifungal immunity by driving CXCL1 production, which recruits CXCR2-expressing neutrophils. Neutrophil-recruiting IL-1b and CXCL1 production is induced in microglia by the fungal-secreted peptide toxin Candidalysin, in a p38-cFos-dependent manner. Importantly, microglia rely on CARD9 for production of IL-1b, via both pro-IL-1b transcriptional regulation and inflammasome activation, and of CXCL1 in the fungal-infected CNS, and we show that microglia-specific CARD9 deletion impairs IL40 1b and CXCL1 production and neutrophil recruitment, and increases CNS fungal proliferation. Our data reveals an intricate network of host-pathogen interactions that promotes CNS antifungal immunity and provides novel mechanistic insights into how human CARD9-deficiency causes CNS fungal disease.
AB - The C-type lectin receptor/Syk adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human CARD9-deficiency causes fungal-specific CNS-targeted infection susceptibility. We previously showed that CARD9 is required for neutrophil recruitment to the fungal-infected CNS, which mediates fungal clearance. Here, we investigated host and pathogen factors that promote protective neutrophil recruitment during Candida albicans CNS invasion and examined their dependence on CARD9 for in vivo induction. We show that IL-1b is essential for CNS antifungal immunity by driving CXCL1 production, which recruits CXCR2-expressing neutrophils. Neutrophil-recruiting IL-1b and CXCL1 production is induced in microglia by the fungal-secreted peptide toxin Candidalysin, in a p38-cFos-dependent manner. Importantly, microglia rely on CARD9 for production of IL-1b, via both pro-IL-1b transcriptional regulation and inflammasome activation, and of CXCL1 in the fungal-infected CNS, and we show that microglia-specific CARD9 deletion impairs IL40 1b and CXCL1 production and neutrophil recruitment, and increases CNS fungal proliferation. Our data reveals an intricate network of host-pathogen interactions that promotes CNS antifungal immunity and provides novel mechanistic insights into how human CARD9-deficiency causes CNS fungal disease.
KW - Animals
KW - Brain/immunology
KW - CARD Signaling Adaptor Proteins/genetics
KW - Candida albicans/immunology
KW - Candidiasis/genetics
KW - Chemokine CXCL1/genetics
KW - Cytokines/genetics
KW - Host-Pathogen Interactions/immunology
KW - Inflammasomes/genetics
KW - Interleukin-1beta/genetics
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Microglia/immunology
KW - Neutrophil Infiltration/genetics
KW - Neutrophils/immunology
KW - ACTIVATION
KW - SUSCEPTIBILITY
KW - ASPARTYL PROTEINASES
KW - CENTRAL-NERVOUS-SYSTEM
KW - INFLAMMATORY MONOCYTES
KW - ASTROCYTES
KW - DEFICIENCY
KW - HOST PROTECTION
KW - FUNGAL-INFECTIONS
KW - CELL
UR - http://www.scopus.com/inward/record.url?scp=85064541511&partnerID=8YFLogxK
UR - http://www.mendeley.com/research/card9-microglia-promote-antifungal-immunity-via-il1%CE%B2-cxcl1mediated-neutrophil-recruitment
U2 - 10.1038/s41590-019-0377-2
DO - 10.1038/s41590-019-0377-2
M3 - Article
C2 - 30996332
VL - 20
SP - 559
EP - 570
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
ER -