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IRE1α Regulates Macrophage Phagocytosis In Immune Thrombocytopenia Through NR1D1 mRNA Decay And Lysosomal Biogenesis

ABSTRACT: Introduction:Macrophage phagocytosis is crucial for cellular homeostasis and is tightly regulated by stress responses. The ER stress sensor IRE1α, a key unfolded protein response (UPR) regulator, is well-studied, but its role in phagocyte homeostasis remains unknown.Objectives:This study investigates whether IRE1α regulates phagocytosis in macrophages and explores its underlying mechanism, aiming to identify potential therapeutic targets for phagocytosis-related disorders.Methods:We examined IRE1α activation in macrophages during phagocytosis of dextran or platelets. Myeloid-specific IRE1α-knockout mice were used to assess phagocytic function. Mechanistic studies included RIDD analysis to identify IRE1α-dependent mRNA degradation. A mouse model of immune thrombocytopenia (ITP) was employed to evaluate platelet clearance, with pharmacological NR1D1 inhibition (SR8278) tested as a rescue strategy.Results:Phagocytosis specifically activates IRE1α in macrophages, where it maintains phagocytic homeostasis. IRE1α deficiency led to excessive phagocytosis due to uncontrolled lysosomal biogenesis. Mechanistically, IRE1α degrades Nr1d1 mRNA via its RNase activity, suppressing lysosomal expansion. In ITP mice, IRE1α deficiency worsened platelet clearance, while SR8278 treatment rescued this defect.

ORGANISM(S): Mus musculus

PROVIDER: GSE305695 | GEO | 2026/02/05

REPOSITORIES: GEO

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