IL-12p40 deletion reduces M1 macrophage polarization and alleviates cardiac remodeling via regulating Th17 cells differentiation, but not γδT 17 cells, in TAC mice.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Cell Differentiation* ; Interleukin-12 Subunit p40*/metabolism ; Interleukin-12 Subunit p40*/genetics ; Macrophages*/immunology ; Macrophages*/metabolism ; Mice, Inbred C57BL* ; Mice, Knockout* ; Th17 Cells*/immunology ; Ventricular Remodeling*; Animals ; Male ; Mice ; Cell Polarity/drug effects ; Gene Deletion ; Interleukin-17/metabolism ; Receptors, Antigen, T-Cell, gamma-delta/metabolism ; Receptors, Antigen, T-Cell, gamma-delta/genetics
    • Abstract:
      Background: The interleukin (IL) -12 p40 subunit is the common subunit of IL-12 and IL-23. It affects the immune inflammatory response, which may be closely related to cardiac remodeling. In this study, the regulatory effect of IL-12p40 knockout (KO) on cardiac remodeling was investigated, and the underlying mechanism was explored.
      Methods and Results: Mice were subjected to transverse aortic constriction (TAC) to establish a model of cardiac remodeling. First, IL-12p40 was deleted to observe its effects on cardiac remodeling and cardiac inflammation, and the results showed that IL-12p40 deletion reduced both T helper 17 (Th17) and γδT17 cell differentiation, decreased proinflammatory macrophage differentiation, alleviated cardiac remodeling, and relieved cardiac dysfunction in TAC mice. Next, we explored whether IL-17 regulated TAC-induced cardiac remodeling, and the results showed that IL-17 neutralization alleviated proinflammatory macrophage differentiation and cardiac remodeling in IL-12p40 knockout mice and WT mice. Neutralization with cluster of differentiation 4 receptor (CD4) and γδ T-cell receptor (γδTCR) antibodies inhibited pro-inflammatory macrophage polarization and improved cardiac remodeling, and CD4 neutralizing antibody (NAb) had more significant effects. Finally, adoptive transfer of Th17 cells aggravated proinflammatory macrophage differentiation and cardiac remodeling in TAC-treated CD4 KO mice, while neutralization with the IL-12p40 antibody alleviated these pathological changes.
      Conclusion: Mainly Th17 cells but not γδT17 cells secrete IL-17, which mediates IL-12p40, promotes the polarization of proinflammatory macrophages, and exacerbates cardiac remodeling in TAC mice. IL-12p40 may be a potential target for the prevention and treatment of cardiac remodeling.
      Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Cardiac remodeling; Interleukin-12p40 deletion; Interleukin-17; Macrophages; Th17 cells and γδT17 cells
    • Accession Number:
      0 (Interleukin-12 Subunit p40)
      0 (Interleukin-17)
      0 (Receptors, Antigen, T-Cell, gamma-delta)
      0 (Il12b protein, mouse)
    • Publication Date:
      Date Created: 20240427 Date Completed: 20240522 Latest Revision: 20240530
    • Publication Date:
      20240530
    • Accession Number:
      10.1016/j.ejphar.2024.176602
    • Accession Number:
      38677538