Megakaryocytes Internalize and Are Activated by Immune Complexes
Year: 2026
Type: article
Abstract: 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 (Fc gamma receptor IIA) 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 (C-X-C motif ligand-2) 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.
Source: Circulation Research
Authors: Florian Puhm, Isabelle Allaeys, Eleonora Petito, Yaqiu Sang, Florian Tupin, Ana dos Santos Pereira Andrade, Etienne Doré, Isabelle Dubuc, Myriam Vaillancourt, Mélanie Dieudé, Marie-Josée Hébert, Bogdan I. Florea, Patrick Trépanier, Valance A. Washington, Yotis Senis, Paul R. Fortin, Alain R. Brisson, Alisa S. Wolberg, Loredana Bury, Louis Flamand, Eric Boilard
Institutions: Université Laval, Centre de recherche du CHU de Québec-Université Laval, CHU de Québec-Université Laval, University of Perugia, University of North Carolina at Chapel Hill, Centre Hospitalier de l’Université de Montréal, Netherlands Proteomics Centre, Héma-Québec, Oakland University, Aix-Marseille Université, Centre de Recherche en CardioVasculaire et Nutrition, Centre National de la Recherche Scientifique, Université de Bordeaux, Chimie et Biologie des Membranes et des Nanoobjects, Institut Polytechnique de Bordeaux
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7164911374