Hemolysis induces IFN-I in liver monocyte/macrophages primarily through TBK1/IKKε, increasing plasma IFN-α levels in SCD.
Heme-driven IFN-I promotes CMo recruitment and differentiation in SCD liver, enhancing antibody-mediated erythrophagocytosis.
Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated vascular injury and tissue damage. Classical monocytes (CMo), which are the most abundant of circulating monocytes, are activated in SCD, but the cause and consequences of activation remain incompletely understood. We found a positive correlation between total plasma heme levels and circulating IFN-α in patients with SCD along with upregulation of the type I Interferon (IFN-I) inducible genes in sort-purified SCD patients' CMo by transcriptome analysis. We demonstrated that hemolysis led to IFN-I expression, predominantly by mouse liver monocyte and macrophages (Mϕ), primarily through Tank kinase binding 1 (TBK1)/IκB kinase-ε (IKKε) but not TLR4. In response to hemolysis-induced IFN-I, mouse CMo migrated to the liver and differentiated into monocyte derived Mϕ, increasing their numbers by 6-fold with acute hemin treatment. Hemolysis-driven IFN-I activity also led to the induction of Fc receptor CD64 expression on monocyte and Mϕ populations, enhancing alloantibody-mediated erythrophagocytosis in SCD both in vivo in mice and in in vitro human cultures. Altogether, these data demonstrate IFN-I response to hemolysis as a novel activation pathway in monocytes and Mϕ in SCD, opening the possibility for development of IFN-I-based diagnostics and therapeutics against alloantibody-mediated erythrophagocytosis.