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CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis

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Abstract

Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.

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Data availability

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

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Funding

This research was supported by the National Natural Science Foundation of China (82171738, 81671563), the Jiangsu Provincial Commission of Health and Family Planning (Q2017001), and the Shenzhen Science and Technology Program (JCYJ20210324115607021).

Author information

Author notes

  1. Zhengxia Wang, Wei Liu and Huidi Hu contributed equally to the work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Zhengxia Wang, Jingxian Jiang, Xijie Zhang, Qi Yuan, Mao Huang & Ningfei Ji

  2. NHC Key Laboratory of Antibody Technique, Jiangsu Province Engineering Research Center of Antibody Drug, Jiangsu Key Laboratory of Pathogen Biology, Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Wei Liu

  3. Department of Pathology, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210029, China

    Huidi Hu, Chen Yang & Mingshun Zhang

  4. The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Xiaofan Yang

  5. Department of Respirology, Shenzhen Children’s Hospital, Shenzhen, 518026, Guangdong, China

    Yanming Bao

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  1. Zhengxia Wang
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Contributions

Conceptualization, XY, MH, YB, NJ, and MZ; formal analysis, ZW, WL, JJ, and MZ; funding acquisition, YB and MZ; investigation, WL and HH; methodology, ZW, WL, HH, JJ, CY, XZ, QY, and XY; project administration, MZ; resources, HH and YB; supervision, MZ; validation, ZW; writing—original draft, ZW; writing—review and editing, YB, NJ, and MZ.

Corresponding authors

Correspondence to Yanming Bao, Ningfei Ji or Mingshun Zhang.

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Supplementary Information

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430_2023_780_MOESM1_ESM.tif

Flow cytometry gating strategy for cells in BALF. Flow cytometry shows the gating strategy of total cells (R1), leukocytes (R2), neutrophils (R3 gate), and macrophages (R4) from BALF (TIF 2170 KB)

430_2023_780_MOESM2_ESM.tif

CD146 deficiency promoted pulmonary inflammation and M2 polarization after challenge with heat-killed (HK) H99 cells. WT and CD146-/- mice were intratracheally infected with 1*104 HK C. neoformans H99 and sacrificed 2 weeks post infection. (A–B) KC and TNF-α in the lung homogenates were measured with ELISA. (C–E) iNOS and Arg1 in the lung were determined with qPCR. *, p<0.05; **, p<0.01; ***, P<0.001; ****, p<0.0001; ns, not significant (TIF 2170 KB)

430_2023_780_MOESM3_ESM.tif

The efficiency of differentiation of BMDMs. The purity of macrophages from cultured BMDMs was gated by CD45+F4/80+ (TIF 1100 KB)

430_2023_780_MOESM4_ESM.tif

Comparative study of some molecules in naïve WT vs CD146 mice. (A-E) IL-4, IL-5, IL-13, IFN-γ, and TNF-α in the lung tissues were measured by qPCR. (F-G) iNOS and Arg1 in lung tissue were measured by qPCR. *, ns, not significant (TIF 1858 KB)

430_2023_780_MOESM5_ESM.tif

Control stains of mouse lung tissue samples. Immunohistochemistry was performed without anti-CD146 and with secondary antibody alone in the tissue samples from mice without or with C. neoformans infection for 3 weeks. Scale bar, 50 μm (TIF 8072 KB)

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Wang, Z., Liu, W., Hu, H. et al. CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis. Med Microbiol Immunol 212, 391–405 (2023). https://doi.org/10.1007/s00430-023-00780-x

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