In:
The Journal of Immunology, The American Association of Immunologists, Vol. 203, No. 1 ( 2019-07-01), p. 236-246
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.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.1900168
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2019
detail.hit.zdb_id:
1475085-5
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