Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

Significance Statement Recent research into the pathophysiology of autosomal dominant polycystic kidney disease indicates that both signaling of primary cilia of tubular cells and immune cell infiltration play key roles. However, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, an important modulator of inflammatory response and a cilia component, is activated in polycystin 1 (PKD1)–deficient tubular cells and is suspected to promote cyst growth. In this work, the authors used murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia to assess STAT3’s role in the disease. They found that, contrary to previous assumptions, STAT3 does not appear to be a critical mediator of cyst growth, but instead acts in a feedback loop that restricts cilia-dependent renal inflammation by repressing proinflammatory cytokines. Background The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression. Method To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines. Results Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro , the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1 -deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. Conclusions STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.