title: SPLUNC1 deficiency enhances airway eosinophilic inflammation in mice.
abstract: Short palate, lung and nasal epithelium clone 1 (SPLUNC1) is enriched in normal airway lining fluid, but is significantly reduced in airway epithelium exposed to a Th2 cytokine milieu. The role of SPLUNC1 in modulating airway allergic inflammation (e.g., eosinophils) remains unknown. We used SPLUNC1 knockout (KO) and littermate wild-type (C57BL/6 background) mice and recombinant SPLUNC1 protein to determine the impact of SPLUNC1 on airway allergic/eosinophilic inflammation, and to investigate the underlying mechanisms. An acute ovalbumin (OVA) sensitization and challenge protocol was used to induce murine airway allergic inflammation (e.g., eosinophils, eotaxin-2, and Th2 cytokines). Our results showed that SPLUNC1 in the bronchoalveolar lavage fluid of OVA-challenged wild-type mice was significantly reduced (P < 0.05), which was negatively correlated with levels of lung eosinophilic inflammation. Moreover, SPLUNC1 KO mice demonstrated significantly higher numbers of eosinophils in the lung after OVA challenges than did wild-type mice. Alveolar macrophages isolated from OVA-challenged SPLUNC1 KO versus wild-type mice had higher concentrations of baseline eotaxin-2 that was amplified by LPS (a known risk factor for exacerbating asthma). Human recombinant SPLUNC1 protein was applied to alveolar macrophages to study the regulation of eotaxin-2 in the context of Th2 cytokine and LPS stimulation. Recombinant SPLUNC1 protein attenuated LPS-induced eotaxin-2 production in Th2 cytokine-pretreated murine macrophages. These findings demonstrate that SPLUNC1 inhibits airway eosinophilic inflammation in allergic mice, in part by reducing eotaxin-2 production in alveolar macrophages.
authors.affiliation: Pulmonary Division, Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Jyoti V
authors.initials: JV
authors.lastname: Thaikoottathil
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Di
authors.forename: Maisha
authors.initials: M
authors.lastname: Minor
authors.forename: Stephanie
authors.initials: S
authors.lastname: Case
authors.forename: Bicheng
authors.initials: B
authors.lastname: Zhang
authors.forename: Gongyi
authors.initials: G
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054423:Chemokine CCL24 / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency* / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C119074:Bpifa1 protein, mouse; D054423:Chemokine CCL24; D006023:Glycoproteins; D018793:Interleukin-13; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D010047:Ovalbumin