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Kidney Week

Abstract: TH-PO277

Myeloid Specific H-Ferritin Mediates Sepsis Induced Inflammation and Organ Injury

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Zarjou, Abolfazl, University of Alabama at Birmingham , Birmingham, Alabama, United States
  • Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Agarwal, Anupam, University of Alabama at Birmingham , Birmingham, Alabama, United States
  • Bolisetty, Subhashini, UAB, Birmingham, Alabama, United States
Background

Sepsis is a severe clinical syndrome that is characterized by profound and dysregulated inflammatory response to infection resulting in end-organ dysfunction distant from the primary site of infection. Despite fundamental findings that have expanded our understanding into the mechanisms that instigate and propagate sepsis and its deleterious effects on various organs including kidney, novel therapeutic agents and modalities have remained elusive. In fact, sepsis remains a leading cause of mortality and acute kidney injury in patients admitted to the intensive care unit. We previously demonstrated that macrophage polarization depends on expression of ferritin heavy chain (FtH) and such expression plays a key role to regulate the cross-talk between macrophages and renal epithelial cells during kidney injury and repair. This led to our hypothesis that macrophage specific FtH may be involved in development and consequences of sepsis.

Methods

Using transgenic mice with conditional deletion of FtH in myeloid cells (FtH LysM-/-), we induced sepsis by a well characterized cecal ligation and puncture method.

Results

Our results demonstrate that myeloid FtH deficiency is associated with hyporesponsiveness to sepsis. We show that specific deletion of FtH in myeloid cells led to ~90% improved survival when compared to FtH LysM+/+ littermates. Furthermore, renal function supported by serum creatinine was significantly more preserved in the FtH LysM-/- mice. In addition, we found decreased level of several pro-inflammatory cytokine expression in major organs, including the kidney. Our mechanistic studies show that myeloid FtH deletion causes derangements in pathways that are crucial in innate immunity and inflammation including NF-κβ, and hypoxia inducible factor.

Conclusion

Overall, our results for the first time signify the paramount importance of myeloid system iron metabolism in sepsis mediated organ injury and identify the central role of FtH in this context. As such, we propose a novel target to mitigate sepsis mediated inflammation and consequent organ injury that is urgently needed given the unacceptable rate of mortality and morbidity related to this devastating clinical condition.

Funding

  • NIDDK Support