Researchers from the Department of Hematology at Tianjin Medical University General Hospital in China have unraveled new details on interferon (IFN)-α signaling in paroxysmal nocturnal hemoglobinuria (PNH).

“Our findings provide crucial insight into the process of reduced IFN-α signal transduction in PNH cells mediated by lipid rafts and suggest that cavin1 [is] a potential target for suppression of IFN-α inflammatory signaling,” the researchers wrote in International Immunopharmacology.

Read more about PNH etiology

They found increased expression of IFN-α in plasma samples from patients with PNH compared to that in control individuals. Moreover, IFN-γ, interleukin 4, interleukin 6, and tumor necrosis factor α were also upregulated in patients with PNH.

Bone marrow mononuclear cells from patients with PNH (n=5) had lower clonogenic activity than those from control individuals (n=5). Additionally, PNH cells seemed to be more resistant to the inhibitory effects of IFN-α as demonstrated by a colony formation assay. Therefore, the researchers suggested that PNH cells might have a growth advantage in unfavorable microenvironments.

Mechanistically, the researchers showed that IFN-α induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2), but this mechanism was attenuated in PIGA-knockout cells (K562-KO cell line). Furthermore, IFN-α receptors, which were located on lipid rafts, were translocated into endosomes in response to IFN-α stimulation. However, this translocation might be impaired in K562-KO cells with defective lipid rafts, resulting in the downregulation of STAT2 and suppression of the inflammatory response.

Furthermore, the researchers demonstrated that the endocytosis of IFN-α and IFN-β receptors was a cavin1-dependent process, although the underlying molecular mechanism remains to be elucidated. Cavin1 was downregulated in patients with PNH (n=10) compared to control individuals (n=10), and its knockdown inhibited IFN-α-induced expression of inflammatory mediators.

Reference

Zeng L, Liu H, Liu Z, et al. Defected lipid rafts suppress cavin1-dependent IFN-α signaling endosome in paroxysmal nocturnal hemoglobinuria. Int Immunopharmacol. Published online January 4, 2023. doi:10.1016/j.intimp.2022.109468