ORCID Profile
0000-0001-7820-1484
Current Organisation
Hudson Institute of Medical Research
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Publisher: Wiley
Date: 2023
DOI: 10.1002/CTI2.1455
Abstract: Inflammasomes induce maturation of the inflammatory cytokines IL‐1β and IL‐18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small‐molecule inhibitors to target inflammasome activity and reduce disease‐associated inflammatory burden. We examined the therapeutic potential of a novel small‐molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome‐mediated inflammation in vivo . In vitro , we characterised ADS032 function, target engagement and specificity. We describe ADS032 as the first dual NLRP1 and NLRP3 inhibitor. ADS032 is a rapid, reversible and stable inflammasome inhibitor that directly binds both NLRP1 and NLRP3, reducing secretion and maturation of IL‐1β in human‐derived macrophages and bronchial epithelial cells in response to the activation of NLPR1 and NLRP3. ADS032 also reduced NLRP3‐induced ASC speck formation, indicative of targeting inflammasome formation. In vivo , ADS032 reduced IL‐1β and TNF‐α levels in the serum of mice challenged i.p. with LPS and reduced pulmonary inflammation in an acute model of lung silicosis. Critically, ADS032 protected mice from lethal influenza A virus challenge, displayed increased survival and reduced pulmonary inflammation. ADS032 is the first described dual inflammasome inhibitor and a potential therapeutic to treat both NLRP1‐ and NLRP3‐associated inflammatory diseases and also constitutes a novel tool that allows examination of the role of NLRP1 in human disease.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2023
Publisher: Springer Science and Business Media LLC
Date: 02-05-2018
DOI: 10.1038/S41598-018-24994-9
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Publisher: Springer Science and Business Media LLC
Date: 30-11-2017
DOI: 10.1038/S41598-017-16317-1
Abstract: Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro , but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX - A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo . Adult ANX - A1 −/− mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24–48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX - A1 −/− mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX - A1 −/− mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX - A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo . Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.
No related grants have been discovered for Sarah Rosli.