Gasdermin D Mediates Inflammation-Driven Pathogenesis of the Myelodysplastic Syndromes

Abstract

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases characterize by cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective hematopoiesis, and increased risk of development of acute myeloid leukemia (AML). Growing evidence revealed the significance of pyroptotic cell death in the inflammatory bone marrow in MDS. However, the detailed mechanisms of pyroptosis in the pathogenesis and progression of MDS remain unknown.Gasdermin D is a pore-forming protein that is cleaved upon inflammasome assembly by inflammatory caspases at the linker between the N-terminus pore-forming domain and the C-terminus autoinhibitory domain. The activation of gasdermin D results in increased cell permeability, cell pyroptosis, and the release of cytokines including Interleukin 1 (IL-1) family. Binding of these cytokines to the IL-1 receptor triggers the activation and release of other pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF).Our group recently established a Diap1 (encoding mDia1) and miR-146a double knockout (DKO) mouse model phenocopying MDS. These two genes are involved in the innate immune signaling and inflammation. DKO mice develop aging-related anemia and thrombocytopenia with over-secretion of pro-inflammatory cytokines. Many DKO mice progress to acute myeloid leukemia (AML) with monocytic differentiation and bone marrow fibrosis at 12 months of age. We found that gasdermin D is upregulated and activated (cleaved) in the bone marrow and spleens of the DKO mice. To study the role of gasdermin D in MDS, we crossed DKO mice with gasdermin D knock out mice to generate gasdermin D, mDia1, miR-146a triple knock out (TKO) mice. Gasdermin D knock out in the background of DKO significantly antagonized the increase of leukocyte count, especially the monocyte count, in the aging mice, and partially rescued the anemia. We transplanted bone marrow from 5-month-old TKO, DKO, and wildtype mice to 5-month-old lethally irradiated mice, respectively, to investigate whether the rescue effect of gasdermin D knock out was hematopoietic cell intrinsic. As expected, TKO bone marrow transplanted (BMT) mice had significantly less leukocyte count compared with DKO BMT mice, the anemia was also ameliorated in TKO BMT mice. More importantly, gasdermin D depletion in hematopoietic cells significantly extended the survival of DKO mice and reverted the progression to AML, suggesting a critical role of GSDMD in the pathogenesis of MDS.These findings indicate that gasdermin D plays a pivotal role in inflammation related MDS development and progression. This is further supported by the evidence that gasdermin D is highly upregulated in patients with MDS in our preliminary immunohistochemical studies in the bone marrow from patients with different types of MDS. Therefore, targeting gasdermin D could be a novel therapeutic approach in the management of MDS. DisclosuresNo relevant conflicts of interest to declare.