LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients
FRENGER Q. 1,2, LUCAS J. 1,2, PETITDEMANGE A. 1,3,5, DEPAUW S. 2, WADIER N. 2, MEYER A. 3,5, HERBER M. 3,5, JAQUEL L. 3,5, MERTZ P. 4,5, FELTEN R. 4,5,6, CHATELUS E. 4,5, DIEUDONNÉ Y. 2,3,5, GUFFROY A. 2,3,5, ARNAUD L. 4,5, POINDRON V. 3,5, GOTTENBERG J. 4,5,6, SIBILIA J. 2,4,5, KORGANOW A. 2,3,5, MARTIN T. 2,3,5, GROS F. 1,2
1 University of Strasbourg, Faculty of Life Sciences, Strasbourg, France; 2 Inserm UMR_S 1109 - Immuno-Rhumatologie moléculaire, University of Strasbourg, Strasbourg, France; 3 Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 4 Department of Rhumatology, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 5 University of Strasbourg, Faculty of Medecine, Strasbourg, France; 6 CNRS UPR3572 - Immunology, Immunopathology and Therapeutic Chemistry, Institute of Molecular and Cellular Biology, University of Strasbourg, Strasbourg, France
Autophagy is a fundamental catabolic process performed by a network of autophagy related (ATG) proteins. Some ATG proteins coordinate parallel roles in so-called “noncanonical” autophagy such as LC3-associated phagocytosis (LAP). Both autophagy and LAP share key functions in immunity and inflammation and have been linked with auto-immune diseases. Systemic sclerosis (SSc) is an auto-immune disease of unknown etiology characterized by excessive and often progressive fibrosis in skin and multiple internal organs linked with an aberrant immune activation. Several polymorphisms of genes coding for ATG proteins, particularly in ATG5, are more frequent in SSc patients. We hypothesized that autophagy and/or LAP could be dysregulated in immune cells from SSc patients. No defect of canonical autophagy was found in lymphocytes and monocytes isolated from peripheral blood mononuclear cells of SSc patients. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess LAP activity. While macrophage polarization appears similar than in healthy donors, we showed that LAP is downregulated in SSc patients. We now need to understand the molecular mechanisms underlying LAP dysregulations. Future investigations leading to the discovery of LAP modulating drugs could then open new therapeutic options for SSc treatment.