Kidney Week

Abstract: PO0384

Resident Macrophages Limit IL-6 generation to Protect Against Septic AKI

Session Information

• AKI: Mechanisms of Injury
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Privratsky, Jamie, Duke University School of Medicine, Durham, North Carolina, United States

Jamie Privratsky, MD, PhD

• Ren, Jiafa, Duke University School of Medicine, Durham, North Carolina, United States

Jiafa Ren,

• Fradin, Hélène, Duke University School of Medicine, Durham, North Carolina, United States

Hélène Fradin,

• Lu, Xiaohan, Duke University School of Medicine, Durham, North Carolina, United States

Xiaohan Lu,

• Morris, Benjamin Tobias, Duke University School of Medicine, Durham, North Carolina, United States

Benjamin Tobias Morris,

• Souma, Tomokazu, Duke University School of Medicine, Durham, North Carolina, United States

Tomokazu Souma,

• Crowley, Steven D., Duke University School of Medicine, Durham, North Carolina, United States

Steven D. Crowley,

Background

The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. There are currently no treatments for septic AKI. Intra-renal macrophages include both tissue-resident (CD11b^mid, F480^hi) and infiltrating (CD11b^hi, F480^lo) populations. The role of resident and infiltrative macrophages in septic AKI pathogenesis remains unclear. As resident macrophages are reported to contribute to tissue repair following injury, we hypothesized that selective depletion of resident macrophages would worsen septic AKI.

Methods

Resident macrophages were selectively depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1^dtr/wt (RM KO mice) compared to CD11cCre(-)/CX3CR1^dtr/wt (RM WT) mice. RM WT and RM KO mice were subjected to sham or cecal ligation and puncture (CLP) sepsis. Kidney injury was assessed by serum creatinine and histologic injury scoring. Cytokine mRNA and protein levels in the serum and kidney were measured by RT-PCR and ELISA. Fluorescent cell-sorting and single cell RNA sequencing were used to profile gene expression following CLP in various intra-renal cell lineages.

Results

After CLP, resident macrophages expressed high levels of anti-inflammatory genes including interleukin 1 receptor antagonist (IL1rn), known to suppress IL6 generation. Compared to RM WT mice, RM KO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine (0.17 +/- 0.08 vs 0.41 +/- 0.17 mg/dl, p<0.001-Fig. 1) and histologic injury (median injury score 0 vs 1, p=0.02). Furthermore, RM KO mice elaborated higher circulating and kidney IL-6 levels. In turn, anti-IL6 therapy ameliorated septic AKI in RM KO mice (Fig. 1).

Conclusion

Resident macrophages protect against septic AKI by limiting IL6 generation. Production of anti-inflammatory IL1rn by resident macrophages may limit tissue damage by constraining IL-6 generation in the septic kidney.

Funding

• NIDDK Support