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Inactive rhomboid protein 2 (iRhom2) regulates ADAM17-mediated shedding of tumor necrosis factor-α (TNF-α) from immune cells. We previously showed that iRhom2 deficiency attenuates early atherosclerosis in mice. This study aimed to characterize the impact of iRhom2 deficiency on macrophage phenotype and function. Bone marrow-derived macrophages (BMDMs) from iRhom2−/− and iRhom2+/+ mice were analyzed for proliferation, phagocytosis, survival of cytotoxic stress, and polarization. Cytokine secretion after LPS stimulation was quantified, and iRhom2 expression under atherogenic stimuli was assessed. Conditioned media from BMDMs (BMDMcM) were applied to human aortic endothelial cells (HAoECs) to evaluate adhesion molecule expression and monocyte adhesion. iRhom2 deficiency did not affect BMDM proliferation, phagocytosis, survival, or polarization marker expression. iRhom2 expression was upregulated in iRhom2+/+ BMDMs by atherogenic stimulation. Following LPS stimulation, TNF-α secretion was decreased and IL-10 secretion was increased in iRhom2−/− compared with iRhom2+/+ BMDMs. HAoEC expression of adhesion molecules—ICAM-1, VCAM-1, and E-selectin—was attenuated after exposure to iRhom2−/− compared with iRhom2+/+ BMDMcM. Monocyte adhesion to HAoECs was reduced following treatment with iRhom2−/− BMDMcM; TNF-α neutralization abolished this effect, indicating TNF-α dependency. iRhom2 deficiency in BMDMs selectively alters macrophage inflammatory cytokine secretion without affecting basal macrophage functions, thereby reducing endothelial activation and monocyte adhesion. These findings identify iRhom2 as a regulator of macrophage–endothelial crosstalk and a potential target to modulate inflammation in atherogenesis.
Hannemann et al. (Sat,) studied this question.