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Macrophage junctional adhesion molecule-like (JAML) protein promotes NLRP3 inflammasome activation in the development of atherosclerosis

Cell Death & Differentiation (2025)Cite this article

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Abstract

Inflammation plays a crucial role in the progression of atherosclerosis. Junctional adhesion molecule-like protein (JAML), a type-I transmembrane glycoprotein, activates downstream signaling pathways. However, the precise role of macrophage-derived JAML in inflammation and atherosclerosis remains unclear. This study aimed to generate mice with macrophage-specific deletion or overexpression of JAML, with the focus of assessing its impact on macrophage function and elucidating its regulatory mechanism in atherosclerosis. High-throughput data screening was employed to investigate JAML expression in atherosclerosis, and macrophage-specific JAML-knockout and transgenic mice models were utilized to examine the effects of JAML on atherosclerosis. Furthermore, the role of JAML was assessed using Oil Red O staining, RNA-sequencing analysis, and co-immunoprecipitation techniques. Increased JAML expression was observed in macrophages from both mice and patients with atherosclerosis. Macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, whereas macrophage-specific JAML overexpression exacerbated these conditions. Mechanistically, JAML deletion inhibited inflammation by decreasing nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, which consequently suppressed the nuclear factor kappa B (NF-κB) pathway and NLRP3 inflammasome activation. Taken together, these findings demonstrate that macrophage-expressed JAML facilitates the progression of atherosclerosis by activating the NF-κB pathway and NLRP3 inflammasome through nuclear migration and phosphorylation of PKM2. Notably, our study revealed a novel mechanism for the regulation of NLRP3 inflammasome activation in atherosclerosis. Therefore, targeting JAML may be an effective treatment strategy for atherosclerosis, a condition characterized by chronic inflammation.

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Fig. 1: Increased JAML expression in atherosclerotic lesions of mice and humans.
Fig. 2: Macrophage-specific JAML knockout attenuates atherosclerosis development in ApoE−/− mice.
Fig. 3: Macrophage-specific JAML over-expression promotes atherosclerosis development in ApoE−/− mice.
Fig. 4: Macrophage-specific JAML deficiency inhibits NLRP3 inflammasome activation in vivo.
Fig. 5: Macrophage-specific JAML deficiency inhibits NLRP3 inflammasome activation in vitro.
Fig. 6: Macrophage-specific JAML overexpression promotes NLRP3 inflammasome activation.
Fig. 7: JAML promotes NLRP3 inflammasome activation via the NF-κB pathway.
Fig. 8: JAML interacts with PKM2 to regulate the activation of the NF-κB signaling pathway.

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Data availability

Original data of RNA-sequencing are available from the NCBI Gene Expression Omnibus (GEO) database under accession number GSE287332.

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Funding

This work was supported by grants of the National Natural Science Foundation of China (Nos. 81100207), the Natural Science Foundation of Shandong Province (ZR2024ZD23 and ZR2024ZD09) and the Taishan Scholar Project of Shandong Province of China (No. tstp20240852).

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  1. These authors contributed equally: Huiliang Cui, Lin Xie, Hanlin Lu.

Authors and Affiliations

  1. State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

    Huiliang Cui, Lin Xie, Hanlin Lu, Fei Xue, Zhenguo Wu, Li Liu, Lei Qiao, Cheng Zhang, Wencheng Zhang & Jianmin Yang

  2. Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China

    Cheng Cheng

  3. Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China

    Cheng Zhang

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Contributions

JY, WZ and CZ conceived, designed the study, and revised the pre-final manuscript and final approval of the version. HC, LX and HL contributed to data acquisition, analysis and writing of the manuscript. CC, FX, ZW, LL and LQ participated in data curation and statistical analysis. All authors have read the manuscript and provided comments and suggestions.

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Correspondence to Wencheng Zhang or Jianmin Yang.

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All animal experimental protocols adhered to the Management Rules of the Chinese Ministry of Health and were approved by the appropriate Ethics Committee (DWLL-2023-037). All human experimental protocols were approved by the Ethics Committee of Shandong University Qilu Hospital. Written informed consent was obtained from all the participants, and the study was conducted in accordance with the Declaration of Helsinki.

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Cui, H., Xie, L., Lu, H. et al. Macrophage junctional adhesion molecule-like (JAML) protein promotes NLRP3 inflammasome activation in the development of atherosclerosis. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01489-5

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