Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis

Area of Science:

• Immunology
• Cellular Biology
• Infectious Disease

Background:

• Sepsis and trauma induce inflammation, increasing susceptibility to hospital-acquired pneumonia (HAP).
• Macrophage phagocytosis is crucial for controlling bacterial infections.
• Impaired macrophage function contributes to HAP development.

Purpose of the Study:

• To investigate the phagocytic activity of macrophages after inflammation resolution.
• To elucidate the mechanisms behind macrophage dysfunction following pneumonia.
• To explore therapeutic strategies for restoring macrophage phagocytosis.

Main Methods:

• Induction of pneumonia in murine models.
• Assessment of alveolar macrophage (AM) phagocytic capacity post-pneumonia.
• Analysis of epigenetic reprogramming and tolerogenic training in AMs.
• Investigation of the role of Signal-regulatory protein α (SIRPα).
• Evaluation of human monocytes from patients with systemic inflammation.

Main Results:

• Murine AMs showed suppressed phagocytosis for weeks after pneumonia resolution.
• This suppression resulted from epigenetic tolerogenic training, not direct pathogen encounter.
• Secondary immunosuppressive signals mediated this adaptation.
• SIRPα was critical for establishing the tolerogenic microenvironment.
• Human monocytes from systemically inflamed patients exhibited similar reprogramming, persisting for months.
• Antibody blockade of SIRPα restored phagocytosis in human monocytes in vitro.

Conclusions:

• Resolution of pneumonia induces a long-lasting, tolerogenic state in macrophages via epigenetic reprogramming.
• The SIRPα pathway is a key mediator of this immunosuppressive adaptation.
• Targeting SIRPα offers a potential therapeutic strategy to enhance macrophage phagocytosis and prevent HAP in critically ill patients.