Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10

• Published in: Journal of immunotoxicology Vol. 17; no. 1; pp. 153 - 162
• Main Authors: Wyatt, T. A., Nemecek, M., Chandra, D., DeVasure, J. M., Nelson, A. J., Romberger, D. J., Poole, J. A.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Administration, Intranasal; Alveoli; Animals; CD204; Cell Line; Disease Models, Animal; Dust; Dust - immunology; Farmer's Lung - drug therapy; Farmer's Lung - immunology; Farmer's Lung - pathology; Fucoidan; Hog barn dust; Humans; IL-10; Inflammation; Inflammatory diseases; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; Kinases; Leukocytes (neutrophilic); lung; Lung - pathology; Lung Injury - drug therapy; Lung Injury - immunology; Lung Injury - pathology; Lungs; Lymphocytes; macrophage; Macrophages; Macrophages, Alveolar; Macrophages, Peritoneal; Male; Mice; Mice, Knockout; Peritoneum; PKCζ; Polysaccharides - administration & dosage; Primary Cell Culture; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase Inhibitors - administration & dosage; Respiratory tract diseases; Scavenger receptors; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; swine; Therapeutic applications; TNF; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; lung; swine; α; Hog barn dust; macrophage; CD204; PKCζ; TNF; IL-10
• ISSN: 1547-691X; 1547-6901; 1547-6901
• DOI: 10.1080/1547691X.2020.1776428

Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated in vitro with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced in vivo lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in in vivo HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. In vitro rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following in vitro HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.