Role of cilia inflammatory signaling in kidney diseases and response to bacteria – BACIL

Sensing chemical and mechanical cues derived from the urinary flow, the primary cilium projects into the lumen of kidney tubules, where they behave as a signaling platform regulating tissue homeostasis. Mutations in genes encoding ciliary proteins are the leading genetic cause of end-stage kidney disease. These “renal ciliopathies” are characterized by the development of interstitial fibrosis that predominates in nephronophthisis (NPH) and/or renal cysts that predominate in autosomal dominant polycystic kidney disease (ADPKD). To date, the pathways linking altered primary cilia function to progressive kidney scarring remain poorly defined and therapeutic options allowing patients to escape end-stage kidney disease are lacking.

We recently demonstrated that mutations in the ciliary genes responsible for ADPKD and NPH induce inflammatory cytokines leading to an infiltration of the kidney by macrophages (ADPKD and NPH), T cells and neutrophils (NPH), which promote kidney damage. We showed that modulating the Hippo/YAP pathway in kidney tubules modifies the expression of this cilia-regulated inflammation. YAP is a co-transcriptional regulator mediating mechano-responsive gene expression but also controls innate immunity through TBK1 and TAK1 inhibition, two critical activating kinases for the IRF3 and NFkB inflammatory pathways.

The activation of innate immunity receptors that recognize pathogens- and/or damage-associated molecular patterns (PAMPs and DAMPs) plays a major role in the infiltration of tissues by immune cells. Our preliminary data indicate that the primary cilium contributes to the activation of an inflammatory pathway in response to urinary flow obstruction or exposure of tubular cells to bacteria, two situations known to induce PAMPs/DAMPs. We determined, however, that cilia specifically regulate inflammation in response to a subset of enterobacteria, independently of classical PAMPs and that pharmacologic Hippo inhibition drastically reduced the cilia dependent inflammatory response to bacteria. Intriguingly, this inflammatory response is reminiscent of the one observed in NPH.

Based on the literature and our own findings, we hypothesize that kidney tubule primary cilia control a Hippo-regulated inflammatory pathway, which may have emerged to protect the kidney from bacterial infections, but also promotes kidney deterioration in renal ciliopathies and obstructive nephropathies. We propose that bacteria may induce and/or accelerate the course of renal ciliopathies.
This project will explore this hypothesis by implementing 4 objectives:
(i) Dissect the pathway(s) by which primary cilia regulate inflammatory responses
(ii) Determine the role of cilia-regulated inflammatory signaling in NPH
(iii) Determine the role of cilia-regulated inflammatory signaling in defense against pathogens
(iv) Assess the impact of infection on the course of human and mouse renal ciliopathies

The BACIL project will dissect inflammatory pathways regulated by primary cilia for insight into their role in kidney deterioration and defense against pathogens. One of the core aims of the BACIL project is to define novel therapeutic strategies for patients suffering from renal ciliopathies, which represent the main cause of genetic end-stage kidney disease. The BACIL project will explore a completely novel field: the interplay among primary cilia, innate immunity, and host-pathogen interactions. This interdisciplinary project is relevant for several research fields. Indeed, most cells in the organism are ciliated, respond to PAMPs through the induction of inflammatory pathways, and may be exposed to bacteria and other microorganisms on a routine or regular basis. The proposed research will thus bring novel insight with broad potential applications for the homeostasis of systems beyond the urinary tract.