Neutrophil-derived S100A8/A9 impairs megakaryocyte maturation in immune thrombocytopenia

Immune thrombocytopenia (ITP) features autoantibody-mediated platelet clearance, but how inflammatory mediators impair thrombopoiesis remains less defined. Using single-cell and spatial transcriptomics, we identify a neutrophil–megakaryocyte axis in ITP marrow in which neutrophil-derived S100A8/A9 engages TLR4 and activates JNK/c-Jun signaling. This pathway represses the megakaryocyte master regulator GATA1 and constrains maturation. In primary CD34+-derived megakaryocyte cultures, ITP plasma reduces polyploidization, maturation-marker expression, and platelet-like particle release; tasquinimod treatment or TLR4 inhibition partially restores these endpoints. In active and passive ITP mouse models, tasquinimod improves platelet recovery, normalizes marrow megakaryocyte abundance, and dampens MAPK signatures. Together, these complementary data position neutrophils as contributors to thrombopoietic failure in ITP, connect marrow inflammation to defective platelet production, and nominate the S100A8/A9–TLR4–JNK/c-Jun axis as a therapeutic target. Modulating this pathway partially restores megakaryopoiesis and alleviates thrombocytopenia in vivo, supporting pharmacologic targeting of S100A8/A9–TLR4 signaling as a potential adjunct to ITP therapy. Immune thrombocytopenia (ITP) is often attributed to peripheral platelet clearance, but how marrow inflammation suppresses platelet production remains incompletely understood. The authors here show that neutrophil-derived S100A8/A9 activates TLR4–JNK/c-Jun signaling to repress GATA1 in megakaryocytes, impairing megakaryocyte maturation and platelet production.