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

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Phagocytes coordinate inflammation and host defense but can cause tissue damage.
• Respiratory infections often lead to acute respiratory distress syndrome (ARDS), characterized by neutrophil accumulation and lung dysfunction.
• Myeloid cell leukemia 1 (Mcl-1) is an intracellular protein involved in regulating apoptosis.

Purpose of the Study:

• To investigate if targeting Mcl-1 accelerates neutrophil apoptosis and resolves inflammation without compromising bacterial clearance.
• To evaluate the therapeutic potential of Mcl-1 inhibition in models of lung inflammation.

Main Methods:

• Mcl-1 was targeted using a cyclin-dependent kinase inhibitor (AT7519) and a flavone (wogonin).
• Human neutrophils and macrophages were used to assess apoptosis and phagocytosis.
• Neutrophil-dominant lung inflammation was induced in mice using endotoxin or Escherichia coli.
• The resolution interval (Ri) and organ function were measured.

Main Results:

• Mcl-1 downregulation induced human neutrophil apoptosis but not macrophage apoptosis or phagocytosis.
• Targeting Mcl-1 in mice shortened the resolution interval (Ri) of lung inflammation from 19 to 7 hours and improved organ dysfunction.
• In bacterial infection models, Mcl-1 manipulation accelerated resolution (Ri; 50 to 16 hours) and enhanced bacterial clearance.
• Inhibiting Mcl-1 downregulation delayed the resolution of endotoxin-mediated lung inflammation.

Conclusions:

• Targeting inflammatory cell Mcl-1 promotes neutrophil apoptosis and accelerates the resolution of lung inflammation.
• This strategy effectively resolves inflammation without detriment to host defense against bacterial infections.
• Manipulating Mcl-1 represents a promising therapeutic target for infection-associated inflammatory diseases.