title: Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells.
abstract: Mycobacteria are among the most common causes of hypersensitivity pneumonitis (HP), but controversy persists with regard to the involvement of the infectious potency of the organism in mycobacterial HP (hot tub lung). This study aimed to establish a mouse model of hot tub lung to clarify its pathophysiology. Mice were exposed intranasally to formalin-killed Mycobacterium avium from a patient with hot tub lung (HP strain) or chronic pulmonary infection (non-HP strain), and bronchoalveolar lavage fluids and lung tissues were evaluated for allergic inflammation. Dead M. avium HP strain, but not non-HP strain, elicited marked HP-like pulmonary inflammation in wild-type mice. Although the inflammation was induced in mice lacking CD4 or CD8, the induction of HP-like responses was prevented in mice lacking myeloid differentiation factor (MyD)88 or Toll-like receptor (TLR)9. Cultured lung CD11c+ cells responded to M. avium in a TLR9-dependent manner, and reconstitution of TLR9-/- mice with lung CD11c+ cells from wild-type mice restored the inflammatory responses. Further investigation revealed that pulmonary exposure to M. avium HP strain increased the number of lung CD11b+ CD11c+ cells (dendritic cells) through TLR9 signalling. Our results provide evidence that hot tub lung develops via the mycobacterial engagement of TLR9-MyD88 signalling in lung CD11b+ dendritic cells independent of the mycobacterial infectious capacity.
authors.affiliation: Dept of Pulmonary Medicine, Tohoku University Hospital, Aobaku, Sendai, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Daito
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: T
authors.initials: T
authors.lastname: Sakakibara
authors.forename: K
authors.initials: K
authors.lastname: Gomi
authors.forename: T
authors.initials: T
authors.lastname: Damayanti
authors.forename: J
authors.initials: J
authors.lastname: Zaini
authors.forename: N
authors.initials: N
authors.lastname: Tode
authors.forename: M
authors.initials: M
authors.lastname: Kanehira
authors.forename: S
authors.initials: S
authors.lastname: Koyama
authors.forename: S
authors.initials: S
authors.lastname: Fujimura
authors.forename: M
authors.initials: M
authors.lastname: Ebina
authors.forename: K J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: T
authors.initials: T
authors.lastname: Takai
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Nukiwa
mesh_terms: D000368:Aged; D000542:Alveolitis, Extrinsic Allergic / Q000378:metabolism* / Q000382:microbiology*; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis*; D039521:CD11c Antigen / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009161:Mycobacterium / Q000378:metabolism*; D009162:Mycobacterium avium / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9