Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Lamina propria (LP) macrophages maintain tolerance to commensal bacteria via interleukin-10 (IL-10).
• Mechanisms distinguishing bacterial invasion from commensalism are not fully understood.
• The role of specific macrophage subsets in mucosal defense remains unclear.

Purpose of the Study:

• To identify macrophage subsets involved in mucosal defense and inflammatory responses.
• To elucidate the signaling pathways linking mucosal injury to monocyte recruitment.
• To explore potential therapeutic targets for inflammatory conditions of the gut.

Main Methods:

• Characterization of CD169(+) macrophage localization within the LP microenvironment.
• Investigation of monocyte recruitment following mucosal injury.
• Assessment of CCL8's role in inflammation using genetic depletion and antibody neutralization in a mouse model of colitis.

Main Results:

• CD169(+) macrophages are located at the base of the LP, distinct from villus tip macrophages.
• These macrophages secrete CCL8 upon mucosal injury, recruiting inflammatory monocytes.
• Depletion of CD169(+) macrophages or anti-CCL8 treatment significantly reduced colitis symptoms in mice.

Conclusions:

• CD169(+) macrophages represent a critical subset linking mucosal damage to inflammatory monocyte infiltration.
• CCL8 secreted by CD169(+) macrophages acts as an alarm signal during barrier defense collapse.
• Targeting CD169(+) macrophages or CCL8 presents a promising strategy for managing mucosal injury and inflammatory diseases.