BACKGROUND: Receptors that bind antibodies are essential for protective adaptive immune responses against antibody-opsonized pathogens, yet their engagement by antibody-autoantigen complexes can drive chronic inflammation in autoimmune diseases. Megakaryocytes, the precursor cells of platelets, express such receptors. However, their response to immunoglobulin G antibodies remains unclear. METHODS: We used both systemic lupus erythematosus and COVID-19 as relevant examples of autoimmune and infection-driven contexts in which antibodies are involved to characterize human and mouse megakaryocyte responses. RESULTS: We found that megakaryocytes internalized immune complexes composed of autoantigens or SARS-CoV-2. In both human and mouse megakaryocytes, immune complexes triggered the release of chemokines and procoagulant extracellular vesicles. This process required FcγRIIA engagement, downstream Syk (spleen tyrosine kinase) signaling, and protein translation. A detailed analysis revealed that megakaryocyte-derived extracellular vesicles did not contain organelles and were largely indistinguishable from a subset of small-sized extracellular vesicles released by activated platelets. In FcγRIIA-transgenic mice, we analyzed megakaryocytes in both the bone marrow and lungs in a lupus model, whereas megakaryocytes were examined in the lungs in a COVID-19 model. In all cases, immunoglobulins were detected in close proximity to FcγRIIA-expressing megakaryocytes. Notably, the chemokine CXCL2 was increased in FcγRIIA-expressing mice under disease conditions. Tissue spatial analysis revealed that CXCL2 predominantly localized to megakaryocytes, supporting these cells as a major source. Furthermore, SARS-CoV-2 stimulated megakaryocytes to release CXCL2 only in the presence of IgG from SARS-CoV-2 immune individuals, and this response was strictly dependent on FcγRIIA expression. CONCLUSIONS: These findings suggest that megakaryocytes contribute to adaptive immune responses through FcγRIIA-mediated signaling.
Puhm et al. (Tue,) studied this question.