A role for the inflammasome effector caspase-1 in hypoxia-induced pulmonary hypertension

Background: Pulmonary hypertension is a severe complication to chronic lung diseases, often with alveolar hypoxia. Inflammasomes are large multiprotein oligomers consisting of receptor molecules (e.g. NLR), an adaptor protein (ASC) and the effector enzyme caspase-1. Assembly of the inflammasome leads to activation of caspase-1 which cleaves interleukin (IL)-18 and IL-1β to their bioactive forms. Elevated levels of IL-18 and IL-1β are found in patients with pulmonary hypertension. Objective: To study the role of the effector caspase-1 in hypoxia-induced pulmonary hypertension. Methods: WT and caspase-1 −/- mice were exposed to 2 weeks of 10% oxygen. Right ventricular systolic pressure (RVSP) was measured with a microtipped transducer catheter. Muscularization of distal arteries was quantified by immunohistochemistry (IHC) methods on lung sections. PCR and Western blotting were performed for mRNA and protein detection. Results: Caspase-1 −/- mice exposed to hypoxia had significantly lower RVSP and RV weight/tibial ratio than WT hypoxic mice, indicating reduced pulmonary hypertension. Hypoxic caspase-1 −/- mice showed less degree of muscularization of distal pulmonary arteries compared to WT mice exposed to hypoxia. No differences in accumulation of collagen in adventitia were found. Expression of inflammatory mediators was measured, and a robust reduction in IL-6 was measured in mice depleted of caspase-1. IL-6 is the main activator of STAT3 phosphorylation at tyrosine 705 which was significantly reduced in caspase-1 deficiency. Conclusions: Caspase-1 regulates hypoxia-induced pulmonary hypertension through generation of IL-6 and phosphorylated STAT3 leading to muscularization of pulmonary arteries.