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

Abstract

Autophagy-related (ATG) proteins orchestrate canonical autophagy and related pathways, including LC3-associated phagocytosis (LAP). Autophagy and LAP play essential roles in immune homeostasis and regulation. Systemic sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by progressive fibrosis affecting the skin and multiple internal organs, together with profound immune dysregulation. ATG alleles have been proposed as genetic susceptibility factors for SSc, suggesting that defects in autophagy-related pathways may contribute to the disease pathogenesis. We investigated whether canonical autophagy and/or LAP are altered in immune cells from patients with SSc. Autophagy was assessed by measuring LC3-II levels in circulating cells from SSc patients and controls, and autophagic flux was evaluated by flow cytometry following lysosomal inhibition. We then generated monocyte-derived macrophages and performed phagocytosis assays to assess the LAP activity. We evaluated the phagocytic capacity using IgG-coated beads that trigger LAP through Fcγ receptor engagement and measured the proportion of LC3-positive phagosomes (LAPosomes). No major defects in canonical autophagy were found in lymphocytes and monocytes isolated from the peripheral blood of patients with SSc. In contrast, monocyte-derived M0 macrophages from patients with SSc exhibited impaired LC3-associated phagocytosis. Impaired LAP in macrophages may contribute to the defective efferocytosis observed in SSc, thereby promoting persistent inflammation and fibrosis. Our findings identify LAP as a previously unrecognized pathway altered in SSc and suggest that therapeutic strategies aimed at restoring LAP activity may represent a novel approach for disease treatment.