Low-dose pro-resolving mediators temporally reset the resolution response to microbial inflammation

Area of Science:

• Immunology
• Inflammation Resolution Biology

Background:

• Specialized pro-resolving mediators (SPMs) are crucial for resolving inflammation, clearing infections, and promoting tissue regeneration.
• SPMs orchestrate the endogenous resolution response to restore homeostasis during acute inflammation.
• This study investigates how infections impact resolution programs and if repetitive SPM administration can reprogram these responses.

Purpose of the Study:

• To determine if infections initiated during ongoing inflammation alter endogenous resolution programs.
• To investigate the potential of low-dose, repetitive SPM regimens to reprogram the resolution response.

Main Methods:

• Murine peritonitis model using zymosan followed by E. coli infection.
• Analysis of exudate leukocytes, lipid mediators, and SPM profiles via flow cytometry and mass spectrometry.
• Administration of a repetitive low-dose SPM panel (RvD1, RvD2, RvD5, MaR1, RvE2) followed by zymosan challenge.
• Assessment of leukocyte composition, resolution indices, and gene expression via RNA-sequencing.

Main Results:

• E. coli infection initiated temporal SPM production, but prior zymosan-induced inflammation delayed pathogen clearance and altered resolution indices.
• Metabololipidomics revealed distinct SPM clusters (RvD1, RvD5, MaR1) during infectious inflammation and resolution phases.
• Repetitive low-dose SPM administration accelerated PMN clearance and shortened the resolution interval by over 70% in a zymosan-induced inflammation model.
• RNA-sequencing indicated that low-dose SPMs modulated genes and pathways involved in immune response, chemokine clearance, and tissue repair.

Conclusions:

• Infections occurring during ongoing inflammation can reset inflammatory resolution mechanisms through specific SPM clusters.
• Low-dose SPM administration can effectively reprogram innate immune responses and pathways, promoting resolution.
• These findings highlight the therapeutic potential of SPMs in managing complex inflammatory conditions.