Hyaluronan Activation of the Nlrp3 Inflammasome Contributes to the Development of Airway Hyperresponsiveness.

ANALYSIS of variance; ANIMAL experimentation; GENES; HYALURONIC acid; IMMUNOBLOTTING; INFLAMMATION; MICE; OZONE; POLYMERASE chain reaction; RESEARCH funding; RESPIRATORY allergy; T-test (Statistics); ENVIRONMENTAL exposure; DATA analysis software; DESCRIPTIVE statistics

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, caspasel, and Nlrp3 in the biological response to ozone and HA. METHODS: C57BL/6J wild-type mice and mice deficient in ASC, caspasel, 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 caspasel and cleaved IL-1Β as markers of inflammasome activation in isolated alveolar macrophages harvested from BALF from FIA-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 caspasel 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. [ABSTRACT FROM AUTHOR]

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