Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension

Abstract

Pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation are key components of pulmonary arterial hypertension (PAH). Interleukin (IL)-1β binds to IL-1 receptor (R)1, thereby recruiting the molecular adaptor myeloid differentiation primary response protein 88 (MyD88) (involved in IL-1R1 and Toll-like receptor signal transduction) and inducing IL-1, IL-6 and tumour necrosis factor-α synthesis through nuclear factor-κB activation.We investigated the IL-1R1/MyD88 pathway in the pathogenesis of pulmonary hypertension.Marked IL-1R1 and MyD88 expression with predominant PA-SMC immunostaining was found in lungs from patients with idiopathic PAH, mice with hypoxia-induced pulmonary hypertension and SM22-5-HTT(+) mice. Elevations in lung IL-1β, IL-1R1, MyD88 and IL-6 preceded pulmonary hypertension in hypoxic mice. IL-1R1(-/-), MyD88(-/-) and control mice given the IL-1R1 antagonist anakinra were protected similarly against hypoxic pulmonary hypertension and perivascular macrophage recruitment. Anakinra reversed pulmonary hypertension partially in SM22-5-HTT(+) mice and markedly in monocrotaline-treated rats. IL-1β-mediated stimulation of mouse PA-SMC growth was abolished by anakinra and absent in IL-1R1(-/-) and MyD88(-/-) mice. Gene deletion confined to the myeloid lineage (M.lys-Cre MyD88(fl/fl) mice) decreased pulmonary hypertension severity versus controls, suggesting IL-1β-mediated effects on PA-SMCs and macrophages. The growth-promoting effect of media conditioned by M1 or M2 macrophages from M.lys-Cre MyD88(fl/fl) mice was attenuated.Pulmonary vessel remodelling and inflammation during pulmonary hypertension require IL-1R1/MyD88 signalling. Targeting the IL-1β/IL-1R1 pathway may hold promise for treating human PAH.

Pulmonary arterial hypertension and the Enigma code of smouldering inflammation

“…However, despite the rapid understanding of innate and adaptive immune responses and inflammation during the 1980s, it was not until 1995 that HUMBERT et al [2] reported that both IL-1 and IL-6 levels were increased in the plasma of patients with idiopathic pulmonary arterial hypertension (PAH), thus revealing an inflammatory component in the pathogenesis of severe PAH. Ever since the first report by HUMBERT et al[2], the role of inflammation as a cause or consequence of PAH has remained controversial [3] and this ongoing debate has perhaps prevented the pragmatism to design clinical trials to test novel anti-inflammatory therapies in patients with PAH.In the current issue of the European Respiratory Journal, PARPALEIX et al [4] provide one more mechanistic piece of evidence to solve the enigma of aseptic inflammation in PAH and offer another rationale to justify the clinical evaluation of IL-1-based treatment strategies for PAH. The authors demonstrated that the levels of the IL-1 receptor 1 (IL1R1) protein and its adaptor protein MyD88, required for downstream signalling, are increased in the lung tissue samples from patients with idiopathic PAH.…”

“…The work of PARPALEIX et al [4], along with the publication by TIAN et al [8], suggests that macrophages may play a significant role in the still enigmatic signalling cascades of inflammatory reactions involved in the pathogenesis of PAH. Whereas the work by TIAN et al [8] discovered a novel action for macrophage-released leukotriene B4 as an inducer of endothelial cell apoptosis, the work by PARPALEIX et al [4] suggests that macrophages may also contribute to pulmonary vascular inflammation and proliferation, at least partly via IL-1/IL1R1 signalling.…”

“…In the current issue of the European Respiratory Journal, PARPALEIX et al [4] provide one more mechanistic piece of evidence to solve the enigma of aseptic inflammation in PAH and offer another rationale to justify the clinical evaluation of IL-1-based treatment strategies for PAH. The authors demonstrated that the levels of the IL-1 receptor 1 (IL1R1) protein and its adaptor protein MyD88, required for downstream signalling, are increased in the lung tissue samples from patients with idiopathic PAH.…”

“…They also showed that in mice with chronic hypoxia-induced PAH and in rats with monocrotaline-induced PAH, treatment with anakinra, a recombinant IL1R1 antagonist, decreased pulmonary vascular muscularisation, right ventricular systolic pressure and right ventricular hypertrophy. The study by PARPALEIX et al [4] confirmed earlier studies that had demonstrated the increased expression of IL-1α and IL-1β protein levels in monocrotaline-induced pulmonary hypertensive rat lungs and that chronic treatment with anakinra prevented the development of monocrotaline-induced PAH [5]. To further assess causality, PARPALEIX et al [4] challenged both IL1R1 and MyD88 knock-out mice with chronic hypoxia, and showed that genetic ablation of the IL-1β canonical signalling machinery ameliorated the pulmonary vascular response to hypoxia.…”

“…The study by PARPALEIX et al [4] confirmed earlier studies that had demonstrated the increased expression of IL-1α and IL-1β protein levels in monocrotaline-induced pulmonary hypertensive rat lungs and that chronic treatment with anakinra prevented the development of monocrotaline-induced PAH [5]. To further assess causality, PARPALEIX et al [4] challenged both IL1R1 and MyD88 knock-out mice with chronic hypoxia, and showed that genetic ablation of the IL-1β canonical signalling machinery ameliorated the pulmonary vascular response to hypoxia. In vitro, they showed how pulmonary vascular smooth muscle cells treated with anakinra had reduced IL-1β-induced cell proliferation, NF-κB activation (a major inflammatory regulator) and IL-6 expression (an IL-1β-inducible cytokine linked to increased mortality in PAH [6,7]).…”