Conditional macrophage ablation demonstrates that resident macrophages initiate acute peritoneal inflammation

Area of Science:

• Immunology
• Cell Biology

Background:

• The role of resident macrophages in initiating peritoneal inflammation is not well understood.
• Neutrophil recruitment is a key feature of peritoneal inflammation.

Purpose of the Study:

• To determine the role of resident peritoneal macrophages in regulating neutrophil recruitment during experimental peritonitis.
• To investigate the mechanisms by which resident macrophages influence neutrophil infiltration.

Main Methods:

• Development of a novel conditional macrophage ablation transgenic mouse (CD11bDTR) using CD11b promoter-driven human diphtheria toxin (DT) receptor expression.
• Intraperitoneal injection of low-dose DT to ablate resident macrophages (Mphi) in the peritoneum, kidney, and ovary.
• Induction of experimental peritonitis and assessment of neutrophil (PMN) infiltration.
• Adoptive transfer of resident nontransgenic Mphi to rescue PMN infiltration.
• Measurement of CXC chemokine production.

Main Results:

• Conditional Mphi ablation using CD11bDTR mice led to rapid and significant reduction of F4/80-positive Mphi populations.
• Mphi ablation dramatically attenuated PMN infiltration in experimental peritonitis.
• Adoptive transfer of resident Mphi rescued PMN infiltration, confirming the role of resident Mphi.
• Reduced PMN infiltration was correlated with diminished CXC chemokine production at 1 hour.

Conclusions:

• Resident peritoneal macrophages play a critical role in initiating peritoneal inflammation.
• These macrophages are essential for sensing peritoneal microenvironment perturbations and regulating neutrophil infiltration.
• Targeting resident peritoneal macrophages could be a therapeutic strategy for peritoneal inflammatory conditions.