Fibrinogen-like protein 2 controls sepsis catabasis by interacting with resolvin Dp5

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• The mechanisms governing the programmed resolution of inflammation are not fully understood.
• Fibrinogen-like protein 2 (Fgl2) is implicated in inflammatory processes, but its specific role in resolution is unclear.

Purpose of the Study:

• To investigate the temporal regulation and function of soluble (sFgl2) and transmembrane (mFgl2) forms of Fgl2 during inflammation resolution.
• To elucidate the molecular pathways involving Fgl2, microRNAs, metalloproteinases, and resolvins in controlling inflammation.

Main Methods:

• Temporal analysis of sFgl2 and mFgl2 expression during inflammation.
• Investigating the roles of miR-466l, ADAM10, and ADAM17 in Fgl2 regulation.
• Assessing the impact of Fgl2 deficiency and administration on immune cell infiltration, maturation, phagocytosis, and resolvin production.
• Examining the interplay between RvDp5, ALX/FPR2, and sFgl2 secretion.

Main Results:

• Both sFgl2 and mFgl2 levels correlate with inflammatory outcomes.
• miR-466l and metalloproteinases (ADAM10, ADAM17) regulate Fgl2 expression and shedding during inflammation resolution.
• Fgl2 deficiency impairs macrophage function and resolvin (RvDp5) production, while increasing neutrophil infiltration.
• sFgl2 administration reduces neutrophil infiltration, promotes neutrophil apoptosis, and enhances RvDp5 biosynthesis.
• RvDp5 activates ALX/FPR2, stimulating sFgl2 secretion and accelerating inflammation resolution.

Conclusions:

• Fgl2 is a critical endogenous regulator of programmed inflammation resolution.
• A novel pathway involving Fgl2, RvDp5, and ALX/FPR2 synergistically resolves inflammation.
• These findings offer new insights for clinical strategies targeting sepsis and other inflammatory conditions.