| First Author | Mizushina Y | Year | 2019 |
| Journal | J Immunol | Volume | 203 |
| Issue | 1 | Pages | 236-246 |
| PubMed ID | 31109954 | Mgi Jnum | J:276602 |
| Mgi Id | MGI:6315656 | Doi | 10.4049/jimmunol.1900168 |
| Citation | Mizushina Y, et al. (2019) Inflammasome-Independent and Atypical Processing of IL-1beta Contributes to Acid Aspiration-Induced Acute Lung Injury. J Immunol 203(1):236-246 |
| abstractText | 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-1beta 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-1beta(-/-) mice, but not NLRP3(-/-) mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1beta into its 18-kDa mature form (p18-IL-1beta), which was different from the caspase-1-processed 17-kDa form (p17-IL-1beta), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1beta. The production of IL-1beta 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-1beta 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-1beta, we identified D109 as a novel cleavage site of pro-IL-1beta 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-1beta 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-1beta production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI. |
