A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury

Area of Science:

• Immunology
• Nephrology
• Critical Care Medicine

Background:

• Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients.
• Kidney macrophages, including F4/80^hi and CD11b^hi subpopulations, play a role in sepsis pathogenesis, but their specific functions in AKI are unclear.
• F4/80^hi macrophages are implicated in immunomodulation post-injury, prompting investigation into their role in septic AKI.

Purpose of the Study:

• To investigate the role of F4/80^hi macrophages in the development of septic AKI.
• To test the hypothesis that selective depletion of F4/80^hi macrophages exacerbates septic AKI.

Main Methods:

• Utilized CD11cCre(+)/CX3CR1^dtr/wt (F4/80 MKO) mice for selective F4/80^hi macrophage depletion via diphtheria toxin.
• Induced sepsis in F4/80 MKO and control (F4/80 MWT) mice using cecal ligation and puncture (CLP).
• Assessed kidney injury using serum creatinine and histological scoring; analyzed kidney cytokine levels and performed single-cell RNA sequencing.

Main Results:

• F4/80 MKO mice exhibited significantly worsened septic AKI compared to F4/80 MWT controls, indicated by elevated serum creatinine and injury scores.
• Kidneys from F4/80 MKO mice showed increased interleukin-6 (IL-6) levels.
• Single-cell RNA sequencing revealed a macrophage-endothelial cell axis where F4/80^hi macrophages express interleukin-1 receptor antagonist (IL-1RA), limiting endothelial IL-6 production.

Conclusions:

• F4/80^hi macrophages protect against septic AKI by expressing IL-1RA, thereby constraining IL-6 generation from endothelial cells.
• This macrophage-endothelial cell crosstalk represents a novel therapeutic target for mitigating sepsis-induced kidney injury.
• Findings are relevant given the success of anti-IL-6 therapies in COVID-19-associated AKI and endothelial dysfunction.