Pulmonary hypertension (PH) results from complex vessel remodeling involving both pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammatory processes. Both toll-like receptors (TLR) and interleukine-1 receptor (IL1R1) are involved in innate immunity and they share common signaling pathways: their activation results in recruitment of the molecular adaptor Myd88, leading to the activation of NFKB and subsequently synthesis and release of many cytokines including IL-1ß, IL-6 and TNFα.
In this study we question whether reducing PH, it is efficient to target IL1R1 or Myd88.
We first examined expression and localization of IL1R1 and Myd88 in lungs from patient with iPAH or controls, as well as in mice with hypoxic PH. Secondly we evaluated the role for IL1R1 and Myd88 in PH by studying IL1R1-/-, MyD88-/− and WT mice treated daily by Anakinra (selective IL1R1 antagonist) exposed to chronic hypoxia, in comparison with WT mice. PA-SMCs from these mice were studied in vitro.
Marked increase expression of IL1R1 and Myd88 were observed in patients with iPAH and in mice exposed to chronic hypoxia. In contrast to IL1R1, which was widely distributed in the lung, Myd88 was preferentially express in remodeled vessels and in particular in PA-SMC. IL1R1-/-, MyD88-/− and WT mice treated with anakinra were similarly protected against hypoxic PH development, as shown by decreases in right ventricular systolic pressure, Fulton index, muscularization of vessels and proliferative ki67-positive cells in arteries compared to untreated WT mice. The increase in lung perivascular macrophages, IL-1ß and IL-6 associated with hypoxia exposure was abrogated in anakinra-treated WT mice and in IL1R1-/− and MyD88-/− mice. In vitro, the potent IL-1ß-mediated growth-promoting activity on PA-SMCs was abolished by anakinra and by genetic deletion of IL1R1 or MyD88. Interestingly, the growth-promoting effect of IL-1ß was stronger in cells from hypoxic WT mice than control. PA-SMC proliferation induced by conditioned media from alveolar macrophages was potentiated by previous macrophage treatment with IL-1ß.
The IL-1ß/IL1R1/Myd88 axis contributes to PH development, by stimulating PA-SMC growth through both direct and indirect macrophage-mediated effects. IL1R1 or Myd88 inhibition may represent a new option for treating PH.Le texte complet de cet article est disponible en PDF.
Keyword : Circulation