Contribution of the Vascular Smooth Muscle Cell-associated Type I cytokine receptors to Pulmonary Arterial Hypertension: At the interface between inflammation and pulmonary vascular remodeling – CoVeR

Despite major therapeutic advances, pulmonary arterial hypertension (PAH) is still a lethal condition without cure at this time. The associated costs to this disease’s care represent a major burden to the healthcare system and a public health concern. Importantly, no therapeutic agent targets the main disease’s characteristic, namely pulmonary vascular remodeling, which can progressively lead to heart failure and premature death.
Thus, it is urgent to develop therapeutic strategies that can directly target PAH key pathophysiological mechanisms underlying pulmonary vascular remodeling, such as the excessive accumulation of pulmonary arterial smooth muscle cells (PA-SMCs) and increased inflammation that both directly contribute to the progression of the intense pulmonary vascular remodeling.
Type I cytokine receptors (TypeIRs) are transmembrane receptors containing a common amino acid motif (WSXWS) in their extracellular domain that recognizes and responds to cytokines with four a-helical strands. Interestingly, several TypeIR members are known to be overexpressed at the cell surface of PA-SMCs in experimental and human PAH, including among others, receptors for interleukin (IL)-6, leptin (Ob), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although the mechanisms controlling the steady-state cytokine receptor cell surface levels, and consequently the cellular response to cytokines, remain poorly understood, it is well established that ring finger protein 41 (RNF41) and ubiquitin-specific protease 8 (USP8) are involved in trafficking of TypeIR transmembrane proteins.
Interestingly, my preliminary data underline that increased levels of TypeIR could be limited by modulating RNF41 protein in PA-SMCs derived from patients with idiopathic PAH.
The aim of this translational project is to assess whether the modulation of TypeIR protein levels may represent a new, powerful and more specific therapeutic tool. The CoVeR project has two principal work packages (WPs), which address fundamental unanswered questions related to the physiopathobiology of idiopathic PAH:

WP1: Do defects in TypeIR intracellular trafficking in PA-SMCs and/or pericytes contribute to pulmonary vascular remodeling in PAH?
WP2: Can we use TypeIR modulators to stop and/or reverse experimental PAH?
A repertoire of unique tools will be used in this research project: ex vivo studies in cell culture, including PA-SMCs and pulmonary pericytes from patients with PAH and from controls without pulmonary vascular disease; in situ immunohistochemical studies in lung specimens from patients with PAH and controls; transgenic mice or rats overexpressing or lacking specific TypeIRs and in vivo rat models of PH (monocrotaline, chronic hypoxia and SUGEN 5416/chronic hypoxia) as well as in vitro studies using small molecules, siRNA or plasmid to modulate TypeIR protein expression and functions.
This translational project is supported by our INSERM UMR_S 999 organization (headed by Pr Humbert), which involves physicians from the French Referral Center for PAH (headed by Pr Humbert), surgeons from the Thoracic Surgery and Lung Transplantation Department (headed by Pr Fadel) and expert pathologists (Pr Dorfmu¨ller and Dr Ghigna). I also have an access to a large patient database (= 1500 patients), a human tissue bank (= 200 lung samples) and a DNA/plasma biobank (= 400 patients).
The CoVeR project will demonstrate that this integrated approach seeking to modulate TypeIR protein levels represents an attractive pharmacological target to treat PAH, for which no curative treatment is currently available. Since aberrant cytokine signaling underlies numerous pathologies, my findings will be highly relevant not only to idiopathic PAH, but also to the other forms of pulmonary hypertension, as well as all conditions that are associated with typeIR overactivation.