Toll-like receptor (TLR2) Regulates Organic Dust-Induced Airway Inflammation

Abstract

RATIONALE: Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating airway inflammation is not clear. This study investigated the role of Toll-like receptor 2 (TLR2), a pattern recognition receptor for Gram-positive cell wall products, in regulating swine facility organic dust-extract (DE)-induced airway inflammation in mice.METHODS: Using an established murine model of intranasal inhalation challenge, TLR2 knockout (KO) and wild type (WT) mice were challenged with DE or saline once (single exposure) or daily for 2 weeks (repetitive exposure). Outcome measurements included bronchoalveolar lavage (BAL) to quantitate leukocyte influx and cytokine/chemokine expression. Lung tissues were collected for histology. Aiway hyperresponsiveness (AHR) by invasive pulmonary function measurement was conducted.RESULTS: Macrophage and neutrophil influx and select cytokines/chemokines were significantly decreased in BAL of TLR2 KO mice at 5hr and 24hr following a single DE exposure. Following repetitive DE challenge, a significant reduction in BAL total cellularity and neutrophil influx was observed concomitant with a significant decrease in TNF-α, IL-6, CXCL1/KC, but not CXCL2/MIP-2, in TLR2 KO mice as compared to WT mice. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was significantly reduced in TLR2 KO mice following repetitive exposure as compared to WT. AHR to methacholine after dust exposure was similar in both groups.CONCLUSION: The TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming-induced airway inflammatory responses. RATIONALE: Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating airway inflammation is not clear. This study investigated the role of Toll-like receptor 2 (TLR2), a pattern recognition receptor for Gram-positive cell wall products, in regulating swine facility organic dust-extract (DE)-induced airway inflammation in mice. METHODS: Using an established murine model of intranasal inhalation challenge, TLR2 knockout (KO) and wild type (WT) mice were challenged with DE or saline once (single exposure) or daily for 2 weeks (repetitive exposure). Outcome measurements included bronchoalveolar lavage (BAL) to quantitate leukocyte influx and cytokine/chemokine expression. Lung tissues were collected for histology. Aiway hyperresponsiveness (AHR) by invasive pulmonary function measurement was conducted. RESULTS: Macrophage and neutrophil influx and select cytokines/chemokines were significantly decreased in BAL of TLR2 KO mice at 5hr and 24hr following a single DE exposure. Following repetitive DE challenge, a significant reduction in BAL total cellularity and neutrophil influx was observed concomitant with a significant decrease in TNF-α, IL-6, CXCL1/KC, but not CXCL2/MIP-2, in TLR2 KO mice as compared to WT mice. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was significantly reduced in TLR2 KO mice following repetitive exposure as compared to WT. AHR to methacholine after dust exposure was similar in both groups. CONCLUSION: The TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming-induced airway inflammatory responses.