Peptidoglycan from Bacillus anthracis Inhibits Human Macrophage Efferocytosis in Part by Reducing Cell Surface...

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Bacillus anthracis peptidoglycan (PGN) is a critical component of the bacterial cell wall and a pathogen-associated molecular pattern.
• Anthrax pathology involves organ dysfunction, coagulopathy, and increased apoptotic leukocytes, suggesting impaired apoptotic cell clearance.
• Macrophage efferocytosis is crucial for resolving inflammation and preventing secondary damage.

Purpose of the Study:

• To investigate whether B. anthracis PGN inhibits the efferocytic capacity of human monocyte-derived macrophages (MΦ).
• To identify the mechanisms by which PGN affects efferocytosis, including receptor expression and protease activity.

Main Methods:

• Human MΦ were exposed to B. anthracis PGN, and efferocytosis was assessed.
• Cell surface expression of efferocytic receptors was analyzed using flow cytometry.
• The role of ADAM17 protease was investigated using specific inhibitors.
• Analysis of PGN recognition dependence on human serum factors and complement component C3.

Main Results:

• PGN exposure impaired MΦ efferocytosis in a human serum-dependent manner, independent of C3.
• PGN treatment reduced the cell surface expression of key efferocytic receptors, including MERTK, TYRO3, AXL, integrin αVβ5, CD36, and TIM-3.
• Evidence suggested the involvement of ADAM17 protease in PGN-induced receptor downregulation.
• ADAM17 inhibition partially restored efferocytic capacity and cell-surface receptor levels.

Conclusions:

• B. anthracis PGN inhibits efferocytosis by human MΦ, requiring human serum factors for optimal recognition.
• The inhibition is partly mediated by reducing the cell surface expression of MERTK and TIM-3.
• Understanding this mechanism provides insight into anthrax pathogenesis and potential therapeutic targets.