TY - JOUR
T1 - Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease
AU - Liu, Yunfeng
AU - Pal, Mouli
AU - Bao, Weili
AU - Shi, Patricia A.
AU - Lobo, Cheryl A.
AU - An, Xiuli
AU - Manwani, Deepa
AU - Zhong, Hui
AU - Yazdanbakhsh, Karina
N1 - Funding Information:
This work was supported in part by grants from the National Institutes of Health National Heart, Lung, and Blood Institute P01 HL149626 (K.Y.) and R01 HL145451 (K.Y.), Hugoton Foundation (H.Z.), and BNY Mellon (C.A.L. and K.Y.).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/9/30
Y1 - 2021/9/30
N2 - 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 interferon-α (IFN-α) in patients with SCD along with upregulation of the type I IFN (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 (Mⲫ), 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 Mⲫ, increasing their numbers by sixfold with acute hemin treatment. Hemolysis-driven IFN-I activity also led to the induction of Fc receptor CD64 expression on monocyte and Mⲫ 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 Mⲫ in SCD, opening the possibility for development of IFN-I-based diagnostics and therapeutics against alloantibody-mediated erythrophagocytosis.
AB - 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 interferon-α (IFN-α) in patients with SCD along with upregulation of the type I IFN (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 (Mⲫ), 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 Mⲫ, increasing their numbers by sixfold with acute hemin treatment. Hemolysis-driven IFN-I activity also led to the induction of Fc receptor CD64 expression on monocyte and Mⲫ 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 Mⲫ in SCD, opening the possibility for development of IFN-I-based diagnostics and therapeutics against alloantibody-mediated erythrophagocytosis.
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U2 - 10.1182/blood.2021011629
DO - 10.1182/blood.2021011629
M3 - Article
C2 - 34166491
AN - SCOPUS:85115990493
SN - 0006-4971
VL - 138
SP - 1162
EP - 1171
JO - Blood
JF - Blood
IS - 13
ER -
