CARD9-dependent macrophage plasticity regulates effective fungal clearance
Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-Xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang
Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-Xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang
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Research Article Dermatology Immunology Infectious disease

CARD9-dependent macrophage plasticity regulates effective fungal clearance

Abstract

The role of CARD9 in the pathogenesis of various chronic fungal infections has been established; however, the precise mechanisms underlying the pathobiology of these infections remain unclear. We investigated the specific cellular mechanisms by which CARD9 deficiency contributes to the pathogenesis of chronic fungal infections. Using single-cell RNA-seq, we analyzed the immune cell profiles in skin lesions from both murine and human samples. We focused on macrophage differentiation and signaling pathways influenced by CARD9 deficiency. We found that CARD9 deficiency promoted the differentiation of high levels of triggering receptor expressed on myeloid cells 2 (TREM2hi) monocyte–derived macrophages after fungal stimulation, impairing their antifungal functions and inducing exhaustion-like Th1 cells. Mechanistically, NF-κB pathway activation was restricted in CARD9-deficient macrophages, leading to enhanced CREB activation, which, in turn, exerted a positive regulatory effect on Trem2 expression by activating C/EBPβ. Notably, targeting TREM2 enhanced the antifungal immune response in vivo and in vitro, thereby alleviating the severity of CARD9-deficient subcutaneous dematiaceous fungal infection. Our findings highlight the important role of CARD9 in regulating cutaneous antifungal immunity and identify potential targets for immunotherapy in chronic dematiaceous fungal infections.

Authors

Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-Xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang

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Figure 1

CARD9 is necessary for defense against subcutaneous dematiaceous fungal infection.

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CARD9 is necessary for defense against subcutaneous dematiaceous fungal ...
(A) Natural course of subcutaneous infection with P. verrucosa in WT and Card9–/– mice. (B) Footpad swelling of P. verrucosa–infected WT and Card9–/– mice at different time points after infection (n = 3). (C) The uniform manifold approximation and projection (UMAP) plot presents the projection of 59,396 high-quality cells from 8 scRNA-seq samples, comprising 4 samples each from WT and Card9–/– group. Each point on the plot represents a single cell, with colors varying according to distinct cell types. (D) The stacked bar chart shows the percentage distribution of 10 immune cell types across all samples. The colors representing each cell type are consistent with those shown in C. (E) The pie chart depicts the distribution of Card9+ cells among immune cell subsets within lesional skin. Data were integrated from all samples. Data are representative of 3 independent experiments and are shown as the mean ± SD. ****P < 0.0001, by 2-way ANOVA (B).