Kidney Week

Abstract: TH-PO188

Activation and Targetability of TYMP-IL-6-TF Axis in the Skin Microenvironment in Patients with Uremic Calciphylaxis

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Lazowski, Adam, Boston University, Boston, Massachusetts, United States

Adam Lazowski

• Morrissey, Austin Patrick, Boston University, Boston, Massachusetts, United States

Austin Patrick Morrissey, MSc

• Krinsky, Scott, Mass General Brigham Inc, Boston, Massachusetts, United States

Scott Krinsky

• Brahim Malloum, Abbas, Boston University, Boston, Massachusetts, United States

Abbas Brahim Malloum, MD

• Edwards, Thierry, Boston University, Boston, Massachusetts, United States

Thierry Edwards

• Jose, Asha, Boston University, Boston, Massachusetts, United States

Asha Jose, PhD

• Bouchouari, Houda, Mass General Brigham Inc, Boston, Massachusetts, United States

Houda Bouchouari

• Yin, Wenqing, Boston University, Boston, Massachusetts, United States

Wenqing Yin, MD, PhD, FASN

• Nazarian, Rosalynn, Mass General Brigham Inc, Boston, Massachusetts, United States

Rosalynn Nazarian, MD

• Nigwekar, Sagar U., Mass General Brigham Inc, Boston, Massachusetts, United States

Sagar U. Nigwekar, MD

• Chitalia, Vipul C., Boston University, Boston, Massachusetts, United States

Vipul C. Chitalia, MD, PhD

Background

Calciphylaxis is a rare disease characterized by calcification and thrombosis of subdermal microvessels, resulting in painful necrosis. It is seen predominantly in patients with end-stage kidney disease (ESKD) and has high mortality, elusive pathogenesis, and no approved therapies.

Methods

Sera and skin biopsies of ESKD patients with calciphylaxis were analyzed using O-linked proteomics and spatial transcriptomics, respectively. The validation and mechanistic probing were conducted using an array of techniques, including multiple ELISA, Immunofluorescence, and neutralizing assays.

Results

We demonstrate that the calciphylaxis sera upregulate IL-6, soluble IL-6 receptor (sIL-6R) levels and induce JAK2-STAT3 phosphorylation in the primary human subdermal microvascular endothelial cells (ECs) in a feedforward manner. Spatial transcriptomics and space-constrained probability analyses revealed a gain of proximal and distal IL-6 ligand-receptor interactions in calciphylaxis skin with heterogeneity between vessels, adipocytes, and eccrine glands. Microvessels served as the predominant senders and recipients of IL-6 signaling. Increased ADAM17, sIL-6R, and normal IL-6R levels in the skin microenvironment supported trans-IL-6 signaling in calciphylaxis. Additionally, calciphylaxis vessels showed an upregulation of thymidine phosphorylase (TYMP). Further mechanistic probing in ECs revealed that calciphylaxis serum-induced TYMP expression augmented IL-6 levels, which activated tissue factor (TF), the primary trigger of the extrinsic coagulation cascade. This TYMP-IL-6-TF axis was supported by strong correlations among TYMP, IL-6, and TF in calciphylaxis vessels. Calciphylaxis sera induced higher TF activity in ECs in a manner dependent on serum IL-6 levels and was suppressed by an anti-hIL-6R antibody.

Conclusion

This work, for the first time, identifies TYMP as an IL-6 regulator and characterizes calciphylaxis as a systemic state of high levels of IL-6 and a local state of activation of the TYMP-trans-IL-6-TF loop in the subdermal microenvironment perpetuating the thrombotic phenotype. Our work uncovers IL-6 as a potential biomarker and a therapeutic target for uremic calciphylaxis.

Funding

• NIDDK Support