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CARD9-dependent macrophage plasticity regulates effective fungal clearance
Lu Zhang1,2,3,4, Zhichun Tang5, Yi Zhang1,2,3,4
1Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.
Insights
Cardamine-9 (CARD9) deficiency promotes chronic fungal infections by altering macrophage function and T helper 1 cell responses. Targeting TREM2 can enhance antifungal immunity and reduce infection severity.
Area of Science:
- Immunology
- Mycology
- Cellular Biology
Background:
- Cardamine-9 (CARD9) is crucial for antifungal immunity, but its precise role in chronic fungal infection pathogenesis is unclear.
- Understanding CARD9's mechanisms is vital for developing targeted therapies against persistent fungal diseases.
Purpose of the Study:
- To elucidate the cellular mechanisms by which CARD9 deficiency exacerbates chronic fungal infections.
- To investigate the impact of CARD9 deficiency on macrophage differentiation and T cell responses in fungal skin infections.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of murine and human skin lesions.
- Analysis of macrophage differentiation, signaling pathways (NF-κB, CREB), and T helper 1 (Th1) cell phenotypes.
- In vivo and in vitro studies targeting TREM2.
Main Results:
- CARD9 deficiency promotes TREM2high macrophage differentiation, impairing antifungal activity and inducing exhausted Th1 cells.
- NF-κB pathway activation is restricted, leading to enhanced CREB activation and increased TREM2 expression via C/EBPβ.
- Targeting TREM2 improved antifungal immune responses and reduced disease severity in CARD9-deficient models.
Conclusions:
- CARD9 plays a critical role in regulating cutaneous antifungal immunity.
- TREM2 is a key mediator in CARD9-deficient fungal infections and a potential therapeutic target.
- These findings offer insights into host-pathogen interactions and potential immunotherapies for chronic dematiaceous fungal infections.
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.
