Abstract Independent studies have reported that interferon-β (IFN-β) induces CYP51A1 downregulation leading to lanosterol accumulation; that lanosterol triggers HMG-CoA reductase (HMGCR) downregulation; and that statin-mediated HMGCR inhibition suppresses mast cell activation. Building on these findings, we investigated whether the known mast cell–stabilizing effect of IFN-α/β is driven by this lanosterol-induced HMGCR downregulation. In bone marrow-derived mast cells (BMMCs), IFN-α indeed induced HMGCR downregulation via both ubiquitin-mediated protein degradation and transcriptional suppression, alongside CYP51A1 downregulation and lanosterol accumulation. Co-treatment with terbinafine, a squalene epoxidase inhibitor used to prevent lanosterol synthesis, restored HMGCR expression to control levels and resulted in full recovery of BMMC function. Co-treatment with specific intermediates of the mevalonate pathway (i.e., mevalonolactone, farnesol, and geranylgeraniol) also counteracted the mast cell–stabilizing effect of IFN-α, without altering the HMGCR and CYP51A1 expression levels. These results indicate that attenuating the MVA pathway via lanosterol-induced HMGCR downregulation is directly responsible for the observed IFN-α-induced mast cell stabilization. Notably, IFN-α compromised the cortical actin dynamics necessary for FcεRI-induced LAT-PLC-γ1 signalosome assembly. These dynamics and signalosome assembly were also fully restored by co-treatment with terbinafine or the MVA pathway intermediates, as well as by the F-actin-destabilizing agent cytochalasin D. These findings were validated in vivo using a mouse model of passive cutaneous anaphylaxis and ex vivo mast cell degranulation assays. Together, our study reveals a previously unrecognized mechanism of immune regulation in which IFN-α stabilizes mast cells by impairing cortical actin dynamics through the CYP51A1-lanosterol-HMGCR axis.
Naskar et al. (Fri,) studied this question.