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

Abstract

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 Ifnγ, leading to bone marrow failure. Myelopoiesis is suppressed through Ifnγ-Ifnγr-mediated release of the alarmin, Hmgb1, which disrupts the marrow endothelial niche. Deletion of Ifnγ or Ifnγr 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 Ifnγ receptor. Contrary to current dogma, TIRAP-activated Ifnγ-driven marrow suppression is independent of T cell function or pyroptosis.In the absence of Ifnγ, TIRAP drives myeloproliferation, implicating Ifnγ in suppressing the transformation of bone marrow failure syndromes to myeloid malignancy. These findings reveal novel, non-canonical roles of TIRAP, Hmgb1 and Ifnγ function in the marrow microenvironment,and provide insight into the pathophysiology of preleukemic syndromes.AGGGTCTACGGGGCAATTT; rev-ACAGTCCGTTTCCGGAGTT); mFasL (for-TTTAACAGGGAACCCCCACT; rev-GATCACAAGGCCACCTTTCT); mIfna (for-GACTTTGGATTCCCGCAGGAGAAG; rev-CTGCATCAGACAGCCTTGCAGGTC); mIfnab (for-CCTGCTGGCTGTGAGGAAAT; rev-CTCACTCAGACTTGCCAGCA); mHmgb1 (for-GTTCTGAGTACCGCCCCAAA; rev-GTAGGCAGCAATATcCTTCTC); mIL-4 (for-TTGAACGAGGTCACAGGAGA; rev-AAATATGCGAAGCACCTTGG); mIL-17a (for-CGCAAAAGTGAGCTCCAGA; rev-TGAGCTTCCCAGATCACAGA); mIL-1rn (for-GTGAGACGTTGGAAGGCAGT; rev-GCATCTTGCAGGGTCTTTTC); mTNFSF11 (for-GACTCCATGAAAACGCAGGT; rev-CCCACAATGTGTTGCAGTTC); mIL-13 (for-TGTGTCTCTCCCTCTGACCC; rev-CACACTCCATACCATGCTGC); mIL-1a (for-AGCGCTCAAGGAGAAGACC; rev-CCAGAAGAAAATGAGGTCGG); mIL-27 (for-GTGACAGGAGACCTTGGCTG; rev-AGCTCTTGAAGGCTCAGGG); mCSF1 (for-CCAGGATGAGGACAGACAGG; rev-GGTAGTGGTGGATGTTCCCA); mCCL2 (for-AGGTCCCTGTCATGCTTCTG; rev-GGGATCATCTTGCTGGTGAA); mIL-23a (for-TTGTGACCCACAAGGACTCA; rev-AGGCTCCCCTTTGAAGATGT); mIfna13 (for-CTTTGGATTCCCACAGGAGA; rev-TTCCATGCAGCAGATGAGTC); mIfna2 (for-GCAGATCCAGAAGGCTCAAG; rev-GGTGGAGGTCATTGCAGAAT); mGAPDH (for-TGCAGTGGCAAAGTGGAGAT; rev-TTTGCCGTGAGGAGTCATA); hIFNγR1 (for-CCAGGGTTGGACAAAAAGAA; rev-CGGGATCATAATCGACTTCC); hIFNγR2 (for-TGACAATGCCTTGGTTTCAA; rev-ATCAGCGATGTCAAAGGGAG); mCamp (for-GCTGTGGCGGTCACTATCAC; rev-TGTCTAGGGACTGCTGGTTGA); mTmsb10 (for-CCGGACATGGGGGAAATCG; rev-CCTGTTCAATGGTCTCTTTGGTC); mTmsb4x (for-ATGTCTGACAAACCCGATATGGC; rev-CCAGCTTGCTTCTCTTGTTCA); mAnxa6 (for-