The Regulation of a Pathogenic Macrophage Polarization by IL-10 in Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a devastating genetic disorder that is one of the most common potentially fatal inherited diseases and is the fourth leading cause of end-stage renal disease (ESRD) in the US5,6,7. The most common form of the disease, autosomal dominant PKD (ADPKD) affects up to 1 in 500 and costs $2 billion/year to care for those afflicted. As the name implies, PKD is characterized by the presence of large, fluid-filled cysts that expand within the kidney, distorting and damaging parenchyma and ultimately resulting in loss of kidney function. Currently, there are no FDA-approved treatments for PKD, but there is hope that a thorough understanding of disease pathogenesis will facilitate the development of treatment strategies that target key drivers of disease progression. In this dissertation, I will summarize what is known about clinical and pathologic features of the disease, focusing on ADPKD and a previously underappreciated aspect of disease pathophysiology—the role of inflammation, especially involving innate immune cells known as macrophages. This work will then describe details of investigations undertaken to better understand the genesis of pathologic macrophages in the cystic kidney and their role in disease progression. These studies have revealed the regulatory cytokine IL-10 to play a key role in this process and thus have identified that cytokine and its signaling partners as potential targets for therapeutic intervention in PKD.