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Inflammasome-Independent and Atypical Processing of IL-1β Contributes to Acid Aspiration-Induced Acute Lung Injury

Inflammasome-Independent and Atypical Processing of IL-1β Contributes to Acid Aspiration-Induced Acute Lung Injury

Yoshiko Mizushina, Tadayoshi Karasawa, Kenichi Aizawa, Hiroaki Kimura, Sachiko Watanabe, Ryo Kamata, Takanori Komada, Naoko Mato, Tadashi Kasahara, Shinichiro Koyama, Masashi Bando, Koichi Hagiwara, Masafumi Takahashi

J Immunol. 2019 Jul 1;203(1):236-246.

PMID: 31109954

Abstract:

Inflammation plays a pivotal role in the pathophysiology of gastric aspiration-induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome-driven IL-1β production in a mouse model of acid aspiration-induced inflammation and ALI. Acid aspiration-induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1β-/- mice, but not NLRP3-/- mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1β into its 18-kDa mature form (p18-IL-1β), which was different from the caspase-1-processed 17-kDa form (p17-IL-1β), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1β. The production of IL-1β by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1β production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro-IL-1β, we identified D109 as a novel cleavage site of pro-IL-1β in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress-produced IL-1β was confirmed by its ability to promote p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1β production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP30827997-A	4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride		30827-99-7	Price

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