Lysophosphatidylcholine-induced macrophage polarization imbalance and functional dysregulation in immune thrombocytopenia.

Abstract

Background: The pathogenesis of immune thrombocytopenia (ITP) involves platelet destruction driven by immune dysregulation, notably macrophage dysfunction. Lysophosphatidylcholine (LPC), a class of bioactive lipid, can modulate inflammation and immunity. This study aimed to determine whether LPC (16:0/0:0) reprograms macrophage metabolism and function in ITP, and to evaluate the therapeutic efficacy of dexamethasone (DXM) and atorvastatin (AT).

Methods: Bone marrow (BM) samples were collected from 61 patients with ITP and 46 healthy controls (HCs) at Qilu Hospital of Shandong University between July 2023 and June 2025. Flow cytometry was used to assess macrophage subsets. Untargeted metabolomics and transcriptomics were performed on sorted BM macrophages. The in vitro effects of LPC (16:0/0:0) on interleukin-10 (IL-10) expression, phagocytosis, and T-cell differentiation, as well as the impact of DXM, AT, or their combination, were tested. Passive and active ITP murine models were used for in vivo validation.

Results: ITP patients had significantly elevated M1 macrophages and decreased IL-10 levels compared to HCs. Integrated metabolomic and transcriptomic analyses revealed enrichment in the glycerophospholipid metabolism pathway, identifying LPC (16:0/0:0) as the most significantly elevated metabolite. Elevated LPC (16:0/0:0) levels correlated with severe thrombocytopenia. In vitro , LPC (16:0/0:0) suppressed IL-10 secretion by macrophages and enhanced M1 macrophage phagocytosis of platelets. It also reduced regulatory T cells (Treg) proportions and increased helper T cell (Th) 1, Th2 and Th22 differentiation. Treatment with DXM or AT restored IL-10 levels and inhibited phagocytosis; DXM suppressed Th1 and Th2 differentiation, AT restored Treg proportions. In vivo , LPC (16:0/0:0) decreased platelet counts and promoted M1 macrophage polarization. DXM and AT promoted platelet recovery and macrophage repolarization, with combination therapy demonstrating superior efficacy.

Conclusions: LPC (16:0/0:0) drives ITP pathogenesis by reprogramming macrophage metabolism and function, promoting inflammation and platelet destruction. The DXM-AT combination exerts synergistic therapeutic effects by complementary targeting of metabolic and immune pathways in the LPC-driven pathogenic axis, effectively restoring immune homeostasis.