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

Mucosal Immunol. 2014 Jul;7(4):857-68. doi: 10.1038/mi.2013.102. Epub 2013 Nov 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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