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ResearchIn-Press PreviewDermatologyImmunologyInfectious disease Open Access | 10.1172/JCI188827

CARD9-dependent macrophage plasticity regulates effective fungal clearance

Lu Zhang,1 Zhichun Tang,2 Yi Zhang,1 Wenjie Liu,1 Haitao Jiang,3 Li Yu,3 Kexin Lei,1 Yubo Ma,1 Yang-xin Fu,3 Ruoyu Li,1 Wenyan Wang,3 Fan Bai,2 and Xiaowen Wang1

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Zhang, L. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Tang, Z. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Zhang, Y. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Liu, W. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Jiang, H. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Yu, L. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Lei, K. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Ma, Y. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Fu, Y. in: PubMed | Google Scholar |

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Li, R. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Wang, W. in: PubMed | Google Scholar

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Bai, F. in: PubMed | Google Scholar |

1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China

2Biomedical Pioneering Innovation Center (BIOPIC) and School of Life Science, Peking University, Beijing, China

3School of Basic Medical Sciences, Tsinghua University, Beijing, China

Find articles by Wang, X. in: PubMed | Google Scholar

Published December 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188827.
Copyright © 2025, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 2, 2025 - Version history
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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 aimed to investigate the specific cellular mechanisms by which CARD9 deficiency contributes to the pathogenesis of chronic fungal infections. Using single-cell RNA sequencing (scRNA-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 promotes the differentiation of TREM2high macrophages following fungal stimulation, impairing their antifungal functions and inducing exhaustion-like T helper 1 (Th1) cells. Mechanistically, the 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.

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