Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension

Abstract

Immune mechanisms and autoimmunity seem to play a significant role in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis and/or progression, but the pathophysiology is still unclear. Recent evidence has demonstrated a detrimental involvement of leptin in promoting various autoimmune diseases by controlling regulatory T-lymphocytes. Despite this knowledge, the role of leptin in IPAH is currently unknown. We hypothesised that leptin, synthesised by dysfunctional pulmonary endothelium, might play a role in the immunopathogenesis of IPAH by regulating circulating regulatory T-lymphocytes function.First, we collected serum and regulatory T-lymphocytes from controls, and IPAH and sclerodermaassociated pulmonary arterial hypertension (SSc-PAH) patients; secondly, we recovered tissue samples and cultured endothelial cells after either surgery or transplantation in controls and IPAH patients, respectively.Our findings indicate that serum leptin was higher in IPAH and SSc-PAH patients than controls. Circulating regulatory T-lymphocyte numbers were comparable in all groups, and the percentage of those expressing leptin receptor was higher in IPAH and SSc-PAH compared with controls, whereas their function was reduced in IPAH and SSc-PAH patients compared with controls, in a leptin-dependent manner. Furthermore, endothelial cells from IPAH patients synthesised more leptin than controls.Our data suggest that endothelial-derived leptin may play a role in the immunopathogenesis of IPAH.

Leptin signalling system as a target for pulmonary arterial hypertension therapy

“…Indeed, Ob/ObR-b axis enhances and accelerates atherosclerosis through various mechanisms, including stimulating proliferation of vascular SMCs, intimal monocyte recruitment, macrophage to foam cell transformation, and further secretion of proatherogenic cytokines [8]. Although we know that the circulating Ob level is increased in iPAH patients and may play a role in the disease physiopathology [7,[9][10][11], the translational relevance of Ob/ObR-b axis in pulmonary vascular proliferation and perivascular monocyte/macrophage lineage cell accumulation is still unclear.…”

“…PBMCs from control and iPAH patients, and from rodents, were fluorescently labelled with the following antibodies fluorophore-conjugated monoclonal anti-CD14, anti-CD25 and anti-CD11b (Becton Dickinson, Rungis, France), anti-CD4 (MiltenyiBiotec, Paris, France), and anti-ObR-b (R&D Systems), as previously described [7]. Flow cytometry gating was set as previously described [7].…”

“…Recent investigations provide clear evidence that leptin (Ob), a hypoxia-inducible factor (HIF)-dependent gene, and its main receptor ObR-b contribute to systemic vascular remodelling, in particular in cardiovascular diseases, acting as a proliferative and migratory factor for systemic vascular SMCs, and as a potent immunomodulator for vascular wall inflammatory cell infiltration [4][5][6][7]. Indeed, Ob/ObR-b axis enhances and accelerates atherosclerosis through various mechanisms, including stimulating proliferation of vascular SMCs, intimal monocyte recruitment, macrophage to foam cell transformation, and further secretion of proatherogenic cytokines [8].…”

Hypertension artérielle pulmonaire

“…La déplétion physique ou fonctionnelle des Treg, qui se traduit par un déséquilibre entre cellules effectrices et régulatrices, est un évènement démontré comme central dans le développement des maladies auto-immunes et suffit à rompre la tolérance au soi conduisant aux maladies auto-immunes chroniques. Dans le sang périphérique, des études contradictoires ont rapporté, soit une augmentation des Treg [23,24], soit un pourcentage inchangé de cellules Treg mais dont la fonction est altérée, en lien avec une surexpression de leptine [25]. Dans le poumon, il a été montré une diminution du nombre de Treg Foxp3 + périvasculaires [26].…”

“…• Prédominance féminine [4,12,14] • Association entre maladies inflammatoires, infectieuses et autoimmunes avec l'HTAP • Défaut de cellules T régulatrices [16,[23][24][25][26][27][28] • Présence d'auto-anticorps circulants [8-10, 29-33, 37, 40] • Rôle physiopathologique des auto-anticorps in vitro [30,31] • Néogenèse lymphoïde périvasculaire : follicules tertiaires pulmonaires [17] • Dépôts d'Ig dans les lésions vasculaires [16,17] • Transfert de la maladie de l'animal malade à l'animal sain [39] Étapes décisives restant à explorer …”