Loss of mDia1 Mediates the Development of Del(5q) MDS through Upregulation of the Innate Immune Response and Induction of Neutropenia

mDia1, the diaphanous homolog 1 of Drosophila in mouse, is a formin protein involving in the linear actin polymerization. Recently, our group reported that patients with del(5q) myelodysplastic syndromes (MDS) showed a significantly decreased mDia1 expression. Mice with mDia1 deficiency developed age related hematologic features mimicking human MDS. In these mice, CD14 is aberrantly overexpressed on granulocytes, which sensitized the innate immune response upon the lipopolysaccharide(LPS) injection. Importantly, chronic LPS injection accelerated the development of MDS (Keerthivasan et al Blood 2014). Here we report that 1) the mDia1 knockout (KO) mice also have a hypersensitive innate immune response to damage-associated molecular pattern molecules (DAMPs), which can be partially blocked by CD14/Toll-like receptor 4(TLR4) signaling pathway inhibitors. This is significant since release of DAMPs from necrotic or senescent cells is a common age-related phenomenon. DAMPs are also detected in cancers including MDS. Thus our study may shed lights on how the deregulated innate immune responses get involved in the pathogenesis of MDS in a more pathophysiologically relevant etiology. 2) mDia1 KO mice have an increased Gr1/Mac1 expression on the granulocytes in peripheral blood. We demonstrate that the expression levels of Gr1/Mac1 were not changed in bone marrow granulocytes, suggesting a specific up-regulation of Gr1/Mac1 levels on circulating granulocytes in mDia1 knockout mice. Mac-1, as the predominant β2 integrin on granulocytes, plays key roles in the adhesion of leukocytes to the endothelium, and regulates the cell adhesion, migration, and chemotaxis. In this respect, the mDia1 knockout mice develop serve neutropenia, which could be due to the upregulation of Gr1/Mac1 and increased binding of the cells to intercellular adhesion molecule-1 (ICAM-1). Finally, we revealed the mechanism of Gr1/Mac1 upregulation by showing that loss of mDia1 significantly affected the endocytosis of Gr1 and Mac1 on granulocytes, however, the mRNA levels of Gr1 and Mac1 were not affected. Taken together, these studies reveal a significance of loss of mDia1 in the pathogenesis of del(5q) MDS through upregulation of innate immune response and accelerated granulocyte clearance.