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 4

Antiinflammatory TREM2hi macrophages in lesions from a patient with CARD9 deficiency and phaeohyphomycosis.

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Antiinflammatory TREM2hi macrophages in lesions from a patient with CARD...
(A) UMAP of macrophages and dendritic cells in the samples from the patient with CARD9 deficiency. Each point represents an individual cell, with the proportion of each subset within the total cell population annotated in the graph. (B) The bubble chart shows the mean relative expression of signature genes across the macrophage and dendritic cell subsets. (C) A UMAP plot shows the expression of TREM2 in macrophages within skin tissues obtained from healthy individuals (n = 3). (D and E) Representative staining of TREM2+ macrophages (TREM2 and CD68) in lesions of patients with CARD9 deficiency and control participants. Scale bars: 100 μm (left) and 20 μm (right). The bar plots show the quantification results (E). One data point represents the statistical result of 1 sample (n = 3). HC, healthy control. (F) A UMAP projection displays the cellular distribution of the CD4+ T cell subset, CD8+T_GZMK subset, CD8+T_HAVCR2 subset, and memory T cell subset as depicted in Supplemental Figure 2A; these were categorized into naive, cytotoxic, and exhaustion states based on the expression of marker genes. (G) Violin plots show the exhaustion score (defined by 5 genes: LAG3, TIGIT, PDCD1, CTLA4, and HAVCR2) of 5 T cell subsets. Box plots overlaid on the violins depict the interquartile range and median score for each subset. (H) The bubble chart shows the interactions between the major macrophage subsets and exhaustion-like Th1 cells in the patient with CARD9 deficiency. Data are shown as the mean ± SD. *P < 0.05 and ***P < 0.001, by 2-tailed Student’s t test (E), or by 1-way ANOVA with Tukey’s test (G).