title: A novel mouse model of conditional IRAK-M deficiency in myeloid cells: application in lung Pseudomonas aeruginosa infection.
abstract: Myeloid cells such as macrophages are critical to innate defense against infection. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of TLR signaling during bacterial infection, but the role of myeloid cell IRAK-M in bacterial infection is unclear. Our goal was to generate a novel conditional knockout mouse model to define the role of myeloid cell IRAK-M during bacterial infection. Myeloid cell-specific IRAK-M knockout mice were generated by crossing IRAK-M floxed mice with LysM-Cre knock-in mice. The resulting LysM-Cre+/IRAK-Mfl/wtand control (LysM-Cre-/IRAK-Mfl/wt) mice were intranasally infected with Pseudomonas aeruginosa (PA). IRAK-M deletion, inflammation, myeloperoxidase (MPO) activity and PA load were measured in leukocytes, bronchoalveolar lavage (BAL) fluid and lungs. PA killing assay with BAL fluid was performed to determine mechanisms of IRAK-M-mediated host defense. IRAK-M mRNA and protein levels in alveolar and lung macrophages were significantly reduced in LysM-Cre+/IRAK-Mfl/wtmice compared with control mice. Following PA infection, LysM-Cre+/IRAK-Mfl/wtmice have enhanced lung neutrophilic inflammation, including MPO activity, but reduced PA load. The increased lung MPO activity in LysM-Cre+/IRAK-Mfl/wtmouse BAL fluid reduced PA load. Generation of IRAK-M conditional knockout mice will enable investigators to determine precisely the function of IRAK-M in myeloid cells and other types of cells during infection and inflammation.
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: 2 Office of Academic Affairs and Department of Biomedical Research, National Jewish Health, Denver, CO, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Matsuda
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Berman
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Niccolette
authors.initials: N
authors.lastname: Schaefer
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Stevenson
authors.affiliation: 2 Office of Academic Affairs and Department of Biomedical Research, National Jewish Health, Denver, CO, USA.
authors.forename: James
authors.initials: J
authors.lastname: Gross
authors.affiliation: 2 Office of Academic Affairs and Department of Biomedical Research, National Jewish Health, Denver, CO, USA.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: 3 Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
authors.affiliation: 1 Department of Medicine, National Jewish Health, Denver, CO, USA.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D000818:Animals; D001433:Bacteriolysis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*
chemical_list: D009195:Peroxidase; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: IRAK-M; LysM–Cre; Pseudomonas aeruginosa; infection; lung