LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

Frenger, Q.; Lucas, J.; Petitdemange, A.; Path, L.; Baldeck, N.; Depauw, S.; Giorgiutti, S.; Merlin, H.; Gong, Y.; Meyer, A.; Herber, M.; Jacquel, L.; Mertz, P.; Felten, R.; Chatelus, E.; Dieudonne, Y.; Guffroy, A.; Arnaud, L.; Poindron, V.; Gottenberg, J.-E.; Sibilia, J.; Korganow, A.-S.; Martin, T.; Gros, F.

doi:10.1101/2024.03.21.586112

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bioRxiv · 10.1101/2024.03.21.586112

LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients

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Abstract

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 to autoimmune diseases. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by excessive 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 M0 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. Key messagesO_LIPolymorphisms of autophagy-related genes are associated with several autoimmune and autoinflammatory diseases, including SSc and SLE C_LIO_LIWhile autophagy has been shown to be dysregulated in circulating cells from SLE patients, no information is available for SSc C_LIO_LIWe show here that autophagy is comparable between PBMCs from patients and matched controls C_LIO_LIWe find a strong impartment of LAP, another ATG-dependent mechanism, in monocyte-derived macrophages from SSc patients C_LIO_LIAs LAP is involved in efferocytosis and the regulation of inflammation, we propose that restoring LAP activity could be a therapeutic option to limit fibrosis and inflammation C_LI

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Frenger, Q., Lucas, J., Petitdemange, A., Path, L., Baldeck, N., Depauw, S., Giorgiutti, S., Merlin, H., Gong, Y., Meyer, A., Herber, M., Jacquel, L., Mertz, P., Felten, R., Chatelus, E., Dieudonne, Y., Guffroy, A., Arnaud, L., Poindron, V., Gottenberg, J.-E., Sibilia, J., Korganow, A.-S., Martin, T., Gros, F.. 2024-03-26. LC3-associated phagocytosis is impaired in monocyte-derived macrophages from systemic sclerosis patients. https://doi.org/10.1101/2024.03.21.586112

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