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- Title
Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung.
- Authors
Lucas, C D; Dorward, D A; Tait, M A; Fox, S; Marwick, J A; Allen, K C; Robb, C T; Hirani, N; Haslett, C; Duffin, R; Rossi, A G
- Abstract
Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (Ri) from 19 to 7 h and improved organ dysfunction with enhanced alveolar-capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (Ri; 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation.
- Subjects
MYELOID leukemia; RESPIRATORY distress syndrome; PNEUMONIA treatment; BACTERIAL diseases -- Immunological aspects; PHAGOCYTOSIS; NEUTROPHILS
- Publication
Mucosal Immunology (1933-0219), 2014, Vol 7, Issue 4, p857
- ISSN
1933-0219
- Publication type
Article
- DOI
10.1038/mi.2013.102