title: HoxA10 Terminates Emergency Granulopoiesis by Increasing Expression of Triad1.
abstract: Expression of the E3 ubiquitin ligase Triad1 is greater in mature granulocytes than in myeloid progenitor cells. HoxA10 actives transcription of the gene encoding Triad1 (ARIH2) during myeloid differentiation, but the contribution of increased Triad1 expression to granulocyte production or function is unknown. Mice with bone marrow-specific disruption of the ARIH2 gene exhibit constitutive inflammation with tissue infiltration by granulocytes and B cells. In contrast, disruption of the HOXA10 gene in mice neither constitutively activates the innate immune response nor significantly alters steady-state granulopoiesis. This study explores the impact of HoxA10-induced Triad1 expression on emergency (stress) granulopoiesis. We found that mice with HOXA10 gene disruption exhibited an overwhelming and fatal emergency granulopoiesis response that was characterized by tissue infiltration with granulocytes, but reversed by re-expression of Triad1 in the bone marrow. We determined that HoxA9 repressed ARIH2 transcription in myeloid progenitor cells, antagonizing the effect of HoxA10 on Triad1 expression. Also, we found that differentiation-stage-specific ARIH2 transcription was regulated by the tyrosine phosphorylation states of HoxA9 and HoxA10. Our studies demonstrate a previously undescribed role for HoxA10 in terminating emergency granulopoiesis, suggesting an important contribution by Hox proteins to the innate immune response.
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; and.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; and Jesse Brown Veteran's Administration Medical Center, Chicago, IL 60612.
authors.forename: Ling
authors.initials: L
authors.lastname: Bei
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; and.
authors.forename: Chirag A
authors.initials: CA
authors.lastname: Shah
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; and.
authors.forename: Liping
authors.initials: L
authors.lastname: Hu
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611; and Jesse Brown Veteran's Administration Medical Center, Chicago, IL 60612 e-eklund@northwestern.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000276:immunology; D038042:Myelopoiesis / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D054875:Ubiquitination / Q000276:immunology
chemical_list: D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C097899:homeobox protein HOXA9; D016222:Fibroblast Growth Factor 2; C092119:Hoxa10 protein, mouse; C506697:Arih2 protein, mouse; D044767:Ubiquitin-Protein Ligases