Hyaluronan Activation of the Nlrp3 Inflammasome Contributes to the Development of Airway Hyperresponsiveness
Feifei Feng,1,2 Zhuowei Li,1 Erin N. Potts-Kant,1 Yiming Wu,2 W. Michael Foster,1 Kristi L. Williams,1,3* and John W. Hollingsworth1,4*
1Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, Duke University Medical Center, Durham, North Carolina, USA; 2Department of Occupational and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China; 3School of Nursing, Duke University Medical Center, Durham, North Carolina, USA; 4Department of Immunology, School of Medicine, Duke University Medical Center, Durham, North Carolina, USA
Background: The role of the Nlrp3 inflammasome in nonallergic airway hyperresponsiveness (AHR) has not previously been reported. Recent evidence supports both interleukin (IL) 1β and short fragments of hyaluronan (HA) as contributors to the biological response to inhaled ozone.
Objective: Because extracellular secretion of IL‑1β requires activation of the inflammasome, we investigated the role of the inflammasome proteins ASC, caspase1, and Nlrp3 in the biological response to ozone and HA.
Methods: C57BL/6J wild-type mice and mice deficient in ASC, caspase1, or Nlrp3 were exposed to ozone (1 ppm for 3 hr) or HA followed by analysis of airway resistance, cellular inflammation, and total protein and cytokines in bronchoalveolar lavage fluid (BALF). Transcription levels of IL‑1β and IL‑18 were determined in two populations of lung macrophages. In addition, we examined levels of cleaved caspase1 and cleaved IL‑1β as markers of inflammasome activation in isolated alveolar macrophages harvested from BALF from HA-treated mice.
Results: We observed that genes of the Nlrp3 inflammasome were required for development of AHR following exposure to either ozone or HA fragments. These genes are partially required for the cellular inflammatory response to ozone. The expression of IL‑1β mRNA in alveolar macrophages was up‑regulated after either ozone or HA challenge and was not dependent on the Nlrp3 inflammasome. However, soluble levels of IL‑1β protein were dependent on the inflammasome after challenge with either ozone or HA. HA challenge resulted in cleavage of macrophage-derived caspase1 and IL‑1β, suggesting a role for alveolar macrophages in Nlrp3-dependent AHR.
Conclusions: The Nlrp3 inflammasome is required for the development of ozone-induced reactive airways disease.
Key words: asthma, environment, extracellular matrix, innate immunity, ozone, toll-like receptor.
Environ Health Perspect 120:1692–1698 (2012). http://dx.doi.org/10.1289/ehp.1205188 [Online 24 September 2012]
Address correspondence to J.W. Hollingsworth, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, DUMC 103004, 106 Research Dr., Durham, NC 27710 USA. Telephone: (919) 684-4588. Fax: (919) 684-5266. E-mail: email@example.com
*These authors contributed equally to the content of this manuscript.
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205188).
This work was supported by National Institutes of Health grants ES016126, AI081672, ES020350, and ES020426 (to J.W.H.); AI089756 (to K.L.W.); and an unrestricted educational grant from the China Scholarship Council (to F.F.).
The authors declare they have no actual or potential competing financial interests.
Received 8 March 2012; Accepted 24 September 2012; Online 24 September 2012.
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