The C3-C3aR axis modulates trained immunity in alveolar macrophages

Area of Science:

• Immunology
• Complement System
• Trained Immunity

Background:

• Complement protein C3 is vital for mucosal immune responses, including in the lung, aiding pathogen clearance and inflammation.
• Trained immunity, an enhanced innate immune response after prior exposure, is well-documented, but the complement system's role is unclear.

Purpose of the Study:

• To investigate the role of complement protein C3 in trained immunity.
• To elucidate the mechanisms by which C3 influences trained immunity in alveolar macrophages.

Main Methods:

• In vivo studies using wild-type and C3-deficient mice subjected to trained immunity protocols.
• Ex vivo analysis of alveolar macrophages (AMs) from trained mice, including cytokine/chemokine production assays.
• Pharmacological and genetic inhibition of Complement component 3a receptor (C3aR) to assess its role.
• Measurement of glycolytic activity in trained AMs.

Main Results:

• Trained wild-type mice showed increased pro-inflammatory cytokines and C3a levels upon secondary stimulation, unlike C3-deficient mice.
• C3-deficient AMs exhibited reduced trained immunity responses, which were restored by exogenous C3 via C3aR signaling.
• Trained wild-type AMs displayed enhanced glycolysis, a defect corrected by C3 in a C3aR-dependent manner.

Conclusions:

• Complement protein C3 plays a crucial role in modulating trained immunity in alveolar macrophages.
• C3 influences trained immunity through C3aR signaling, impacting cytokine production and metabolic reprogramming.
• This study reveals a novel function for C3 in the innate immune memory of the lung.