3015 – INCREASED TGFΒ SIGNALING DRIVES CHRONIC BONE MARROW FAILURE AFTER ACUTE INFLAMMATORY STRESS

Abstract

Bone marrow failure (BMF), characterized by either an accelerated decline of hematopoietic stem cell number or chronic inability to sufficiently produce mature blood lineages, can be caused by stress conditions such as after hematopoietic stem cell transplantation (HSCT),myeloablative chemotherapy, or chronic inflammation. However, a clear understanding of how inflammation contributes to BMF is still lacking. TGFβ signaling, a cytokine elevated in the bone marrow following hematopoietic stress, is known to contribute to BMF pathogenesis. To understand how TGFβ signaling and inflammation may cooperate to drive BMF, we used a transgenic mouse model to conditionally over-express an active form of TGFβ1 in hematopoetic cells (Tg-Cre+). Interestingly, after exposure to double-stranded RNA (ie, pIC), Tg-Cre+ mice became pancytopenic and had splenomegaly. They displayed increased hematopoietic progenitors, and cellular dysplasia in BM myeloid, erythroid and megakaryocytic compartments, mimicking BMF/myelodysplastic(MDS)-like disease. These sustained phenotypes occurred only after transient challenge with pIC, thus suggesting that multi-inflammatory hits trigger BMF/MDS-like disease. Mechanistically, TGFβ1 modified a normal pIC response. Normally, pIC causes transient increased HSC cell cycle, associated with a type I Interferon response. Interestingly, we found that pIC also induced activation of mitochondria with elevated mitochondrial membrane potential (MMP), and activation of the inflammasome component caspase 1 in HSC. While HSC MMP in control mice returned to baseline, HSC from Tg-Cre+ maintained higher MMP and caspase-1 activity for up to 3 months after pIC treatment. Thus, transient pIC stimulation in the context of enhanced TGFβ signaling may trigger mitochondrial-mediated innate immune responses that contribute to BMF/MDS disease initiation and progression.