Deficiency of Inactive Rhomboid Protein 2 (iRhom2) Attenuates Macrophage Atherogenicity

Area of Science:

• Immunology
• Cell Biology
• Cardiovascular Research

Background:

• Inactive rhomboid protein 2 (iRhom2) regulates ADAM17-mediated shedding of tumor necrosis factor-α (TNF-α).
• iRhom2 deficiency has been shown to attenuate early atherosclerosis in mouse models.
• The specific impact of iRhom2 on macrophage phenotype and function in the context of atherosclerosis requires further characterization.

Purpose of the Study:

• To investigate the effect of iRhom2 deficiency on macrophage phenotype and function.
• To determine how iRhom2 impacts macrophage-endothelial cell interactions.
• To assess iRhom2's role in regulating inflammatory responses relevant to atherosclerosis.

Main Methods:

• Bone marrow-derived macrophages (BMDMs) from iRhom2 knockout and wild-type mice were analyzed for proliferation, phagocytosis, survival, and polarization.
• Cytokine secretion (TNF-α, IL-10) after LPS stimulation was quantified.
• Human aortic endothelial cells (HAoECs) were treated with conditioned media from BMDMs to assess adhesion molecule expression and monocyte adhesion.

Main Results:

• iRhom2 deficiency did not alter basal BMDM proliferation, phagocytosis, survival, or polarization.
• LPS stimulation led to decreased TNF-α and increased IL-10 secretion in iRhom2-deficient BMDMs.
• Exposure to iRhom2-deficient BMDM conditioned media reduced ICAM-1, VCAM-1, and E-selectin expression on HAoECs, decreasing monocyte adhesion in a TNF-α-dependent manner.

Conclusions:

• iRhom2 deficiency selectively modulates macrophage inflammatory cytokine secretion without affecting basal functions.
• Reduced TNF-α secretion by iRhom2-deficient macrophages decreases endothelial activation and monocyte adhesion.
• iRhom2 is identified as a key regulator of macrophage-endothelial crosstalk and a potential therapeutic target for modulating inflammation in atherosclerosis.