Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung.

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.

• Authors: C D Lucas, D A Dorward, M A Tait, S Fox, J A Marwick, K C Allen, C T Robb, N Hirani, C Haslett, R Duffin, A G Rossi
• Journal: Mucosal immunology (Mucosal Immunol) Vol. 7 Issue 4 Pg. 857-68 (Jul 2014) ISSN: 1935-3456 [Electronic] United States
• PMID: 24280938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide
• Myeloid Cell Leukemia Sequence 1 Protein
• Piperidines
• Pyrazoles
• Caspases

Topics

• Animals
• Apoptosis (drug effects, immunology)
• Caspases (metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Lung (immunology, metabolism, microbiology, pathology)
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Neutrophil Infiltration (immunology)
• Neutrophils (drug effects, immunology, metabolism)
• Piperidines (pharmacology)
• Pneumonia (genetics, immunology, metabolism, microbiology, pathology)
• Pyrazoles (pharmacology)