Histone Deacetylase 11 (HDAC11) Plays as a Novel Transcriptional Regulator in Hematopoiesis under Pathological Conditions

During hematopoiesis, multilineage progenitor cells and the precursors are committed to individual hematopoietic lineages. In normal myelopoiesis, the immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells. However, under tumor burden, these IMCs differentiate into myeloid derived suppressor cells (MDSCs) result in an upregulation of immune suppressive factors1. The development of normal or malignant is tightly controlled by endogenous signals such as transcription factors and epigenetic regulations. HDAC11 is the newest identified members of the histone deacetylase (HDAC) family. Previous study in our group had identified HDAC11 as a negative regulator of interleukin 10 (IL-10) production in antigen-presenting cells(APCs). However, the mechanisms of HDAC11 in normal and malignant hematopoiesis remains unclear. We have uncovered for the first time that in the absence of HDAC11, upon LPS stimulation, neutrophils isolated form mice displays an overproduction of pro-inflammatory cytokines such as TNF-alpha and IL-6 using both mRNA and protein analysis. Strikingly, these HDAC11 KO neutrophils showed a significantly higher migratory and phagocytosis activity, resulting from an overexpression of the migratory receptor and cytokine CXCR/L2. We have performed Chromatin Immunoprecipitation (ChIP) analysis on the neutrophils and discovered that HDAC11 was recruited to the promoter regulatory region of these genes we have identified. Not only does HDAC11 plays a crucial role in the neutrophil function, our group have also found out that lacking of HDAC11 increase the suppressive activity of Myeloid-drived Suppressor Cells (MDSCs). The previous publication of our group had shown that the tumor bearing mice experienced a much more aggressive growth pattern in the HDAC11 KO mice compare with C57BL/6 wild type control. We observed a markedly higher expression of the lineage-specific transcription factor C/EBP-β mRNA in the CD11b+/Ly6G+ granulocytic compartment the CD11b+/Ly6C+ monocytic compartments of HDAC11KO mice relative to control mice. C/EBP-β has been proved to play a crucial role in the MDSCs generation and function2. To explore the mechanism we found out that HDAC11 was recruited to the promoter region of C/EBP-β of the primary myeloid cells. Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator in neutrophils and MDSCs function. In the absence of HDAC11, neutrophils function more pro-inflammatory upon infection. And interestingly, HDAC11 may function as an epigenetic checkpoint of C/EBP-β gene expression in the MDSCs under tumor condition. Our findings will lead to a better understanding of this novel role of HDAC11 in myeloid biology under different pathological conditions