Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

Abstract

words)The inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results 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, while disrupting 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. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

The carboxy‐terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC‐activation

“…Larger numbers and additional studies on the interplay between cyst-lining epithelial signalling and, for example, interstitial inflammatory processes, functional mapping in full-length fibrocystin, and studies on the effects of the observed SRC-induced FC phosphorylation on the non-conserved tyrosine 3992 are required. 15 In summary, we show increased activation of SRC and STAT3 in cyst-lining epithelia of ARPKD kidneys. Mechanistically, our data suggest that the carboxy-terminus of human FC can contribute to control of SRC-activation.…”

“…This activation showed some variability amongst patients with different clinical courses. Larger numbers and additional studies on the interplay between cyst‐lining epithelial signalling and, for example, interstitial inflammatory processes, functional mapping in full‐length fibrocystin, and studies on the effects of the observed SRC‐induced FC phosphorylation on the non‐conserved tyrosine 3992 are required 15 …”

Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner

“…However, while STAT3 activation was increased in Pkd2;Thm1 dko mice, fibrosis as assessed by αSMA staining was not. In contrast to studies suggesting a pathogenic role for increased STAT3 signaling, a recent study has shown that tubular STAT3 activation restricts immune cell infiltration in Pkd1 cko mice 32 . Genetic deletion of Stat3 together with Pkd1 in renal tubular cells slightly reduced cystic burden, but did not ameliorate kidney function and increased interstitial inflammation.…”

IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice

“…A well-characterized role for primary cilia is Hedgehog (Hh) signal transduction, which generally requires primary cilia to potentiate downstream intracellular signaling (17,19). It has been established that the transcription factor signal transducer and activator of transcription 3 (STAT3), which can be activated by various proinflammatory cytokines, promotes ciliogenesis (20)(21)(22). Uterine Stat3 deficiency causes decidualization failure in mice (23,24).…”

“…Both intraflagellar transport protein IFT88 and Joubert syndrome protein ARL13B are required for cilia assembly and Hh signal transduction ( 25 , 26 ), whereas the histone deacetylase HDAC6 and the kinase Aurora A are important for cilia disassembly ( 27 ). The dysfunction of primary cilia results in multisystemic genetic ciliopathies such as polycystic kidney disease ( 21 ). Although recent single-cell transcriptomic analyses indicate that motile cilia are present in endometrial epithelial cells throughout the human menstrual cycle ( 28 , 29 ), whether primary cilia are present in the mammalian uterus remains unsolved.…”