Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy

Area of Science:

• Immunology
• Cardiology
• Cell Biology

Background:

• Inflammatory dilated cardiomyopathy (DCMi) is a significant cause of heart failure in young adults.
• Interleukin-17A (IL-17A) has been identified as a key mediator in DCMi development.
• Understanding the cellular interactions driving DCMi is crucial for therapeutic development.

Purpose of the Study:

• To elucidate the novel pathway involving IL-17A, cardiac fibroblasts (CFs), and myeloid cells in DCMi pathogenesis.
• To investigate the role of CFs and granulocyte-macrophage colony-stimulating factor (GM-CSF) in IL-17A-mediated DCMi.
• To identify potential therapeutic targets within this newly discovered pathway.

Main Methods:

• Utilized Il17ra(-/-) mice to assess the role of IL-17A signaling in DCMi.
• Employed myeloid cell depletion strategies (Ly6Chi MO/MΦ) to evaluate their contribution to DCMi.
• Investigated the molecular mechanisms by which IL-17A stimulates CFs to produce chemokines and cytokines.

Main Results:

• Il17ra(-/-) mice exhibited protection from DCMi, with reduced cardiac infiltration of neutrophils and Ly6Chi monocytes/macrophages (MO/MΦ).
• Depletion of Ly6Chi MO/MΦ significantly protected mice from DCMi.
• IL-17A stimulation of CFs led to the production of myeloid cell-recruiting factors, and IL-17A, via CF-derived GM-CSF, promoted a proinflammatory phenotype in Ly6Chi MO/MΦ.

Conclusions:

• A novel IL-17A-driven pathway involving cardiac fibroblasts and myeloid cells (Ly6Chi MO/MΦ) is critical for DCMi pathogenesis.
• This axis, mediated by CF-derived GM-CSF, promotes inflammation and heart failure.
• The IL-17A-fibroblast-GM-CSF-MO/MΦ axis represents a promising therapeutic target for DCMi and related inflammatory cardiac conditions.