TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the marrow microenvironment

Activation of inflammatory pathways is associated with bone marrow failure syndromes, but how specific molecules impact on the marrow microenvironment is not well elucidated. We report a novel role for the miR-145 target, Toll/Interleukin-1 receptor domain containing adaptor protein (TIRAP), in driving bone marrow failure. We show that TIRAP is overexpressed in various types of myelodysplastic syndromes (MDS), and suppresses all three major hematopoietic lineages.. Constitutive expression of TIRAP in hematopoietic stem/progenitor cells (HSPC) promotes upregulation of Ifn{gamma}, leading to bone marrow failure. Myelopoiesis is suppressed through Ifn{gamma}-Ifn{gamma}r-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifn{gamma} or Ifn{gamma}r blocks Hmgb1 release and is sufficient to reverse the endothelial defect and prevent myelosuppression. In contrast, megakaryocyte and erythroid production is repressed independently of the Ifn{gamma} receptor. Contrary to current dogma, TIRAP-activated Ifn{gamma}-driven marrow suppression is independent of T cell function or pyroptosis. In the absence of Ifn{gamma}, TIRAP drives myeloproliferation, implicating Ifn{gamma} in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifn{gamma} function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/967018v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d033fborg.highwire.dtl.DTLVardef@104bab9org.highwire.dtl.DTLVardef@17ed484org.highwire.dtl.DTLVardef@1b228ed_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract: Model of proposed mechanism of TIRAP-induced BMFConstitutive TIRAP expression in marrow cells releases Ifn{gamma}, which directly impacts on megakaryocyte and erythroid production, but indirectly suppresses myelopoiesis through the release of the alarmin, Hmgb1, which disrupts the marrow endothelial compartment. C_FIG