Modulating inflammation with interleukin 37 treatment ameliorates murine Autosomal Dominant Polycystic Kidney Disease

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a primary cause of kidney failure, characterized by inflammation and cyst development.
• Interstitial inflammation, driven by macrophages, is believed to worsen ADPKD progression.
• Identifying novel therapeutic targets is crucial for managing ADPKD.

Purpose of the Study:

• To evaluate the therapeutic potential of the anti-inflammatory cytokine Interleukin 37b (IL37b) for Autosomal Dominant Polycystic Kidney Disease (ADPKD).
• To investigate the mechanisms by which IL37b might ameliorate ADPKD pathology in preclinical models.

Main Methods:

• Utilized genetic mouse models of early and adult-onset ADPKD.
• Administered transgenic expression and recombinant forms of human IL37b.
• Conducted whole kidney RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq).
• Investigated the role of interferon signaling by blocking type I interferon pathways.

Main Results:

• Transgenic IL37b expression reduced kidney cyst burden in both early and adult-onset ADPKD mouse models.
• Recombinant IL37b administration also decreased cyst burden in early-onset ADPKD mice.
• IL37b induced upregulation of the interferon signaling pathway, originating partly from kidney resident macrophages.
• Blocking type I interferon signaling abrogated the beneficial effects of IL37b, increasing cyst number.

Conclusions:

• IL37b demonstrates therapeutic potential for ADPKD by reducing cyst burden.
• The mechanism involves IL37b-mediated activation of interferon signaling in kidney resident macrophages.
• IL37b represents a promising candidate for novel ADPKD therapies.