Adjuvant conditioning enhances neutrophil function while inducing a suppressive peritoneal macrophage phenotype

Area of Science:

• Immunology
• Vaccinology
• Transplantation Immunology

Background:

• Adjuvants like alum are crucial for enhancing vaccine immunogenicity.
• Previous research showed adjuvant conditioning (AC) with alum delays graft rejection via NLRP3-dependent myeloid-derived suppressor cell (MDSC) expansion.
• The impact of AC on peritoneal cavity cell reprogramming, especially macrophage populations, and subsequent adaptive immunity remains unclear.

Purpose of the Study:

• To investigate the effects of AC on distinct peritoneal macrophage populations (small peritoneal macrophages [SPMs] and large peritoneal macrophages [LPMs]).
• To elucidate the impact of AC on resident macrophages, infiltrating monocytes, and neutrophil recruitment.
• To understand the consequences of AC-induced immune cell reprogramming on innate and adaptive immune responses.

Main Methods:

• In vitro inflammasome activation assays on isolated SPMs and LPMs.
• In vivo analysis of peritoneal cavity cell populations following repeated intraperitoneal alum administration in mice.
• Assessment of macrophage disappearance reaction (MDR) and neutrophil recruitment.
• Evaluation of immune cell reprogramming towards inflammatory or immunosuppressive phenotypes.

Main Results:

• SPMs exhibited greater inflammasome activation susceptibility than LPMs in vitro.
• In vivo, AC induced a NLRP3-dependent MDR in LPMs, linked to aggregate formation and omental migration.
• AC reprogrammed resident macrophages and monocytes to a less inflammatory state, increasing susceptibility to bacterial infections.
• AC promoted neutrophil recruitment with enhanced bacterial killing capabilities.

Conclusions:

• Adjuvant conditioning with alum induces population-specific immune responses within peritoneal macrophages.
• AC leads to significant reprogramming of innate immune cells, including macrophages and neutrophils, with distinct functional outcomes.
• The immunosuppressive environment created by AC, characterized by macrophage reprogramming and altered neutrophil function, suggests potential therapeutic applications for autoimmune diseases and transplant rejection.