IRE1α regulates macrophage phagocytosis in immune thrombocytopenia through NR1D1 mRNA decay and lysosomal biogenesis

Macrophage phagocytosis is essential for immune homeostasis but must be tightly constrained to prevent pathological tissue damage. How cellular stress pathways enforce phagocytic homeostasis remains incompletely understood. Here, we show that phagocytosis selectively activates the endoplasmic reticulum stress sensor IRE1α in macrophages, which functions as a negative regulator of lysosome-driven phagocytic amplification. Using myeloid-specific IRE1α-deficient mice and pharmacological inhibition, we demonstrate that loss of IRE1α RNase activity leads to excessive phagocytosis through unchecked lysosomal biogenesis. Mechanistically, phagocytosis-activated IRE1α directly degrades Nr1d1 mRNA via regulated IRE1α-dependent decay (RIDD), thereby restraining NR1D1-driven lysosomal expansion. Disruption of this IRE1α-NR1D1 axis exacerbates macrophage-mediated platelet clearance and accelerates disease progression of immune thrombocytopenia (ITP). Reduced ERN1 expression and IRE1α activity are observed in monocytes from patients with ITP. Pharmacological inhibition of NR1D1 or lysosomal activity rescues thrombocytopenia. Together, these findings establish the IRE1α-NR1D1-lysosome axis as a therapeutically actionable pathway in phagocytosis-driven diseases.