| Caspase-8 Promotes Pulmonary Hypertension by Activating Macrophage-Associated Inflammation and IL-1 beta (Interleukin 1 beta) Production |
| Author |
Rong, WW; Liu, CC; Li, XM; Wan, NF; Wei, LJ; Zhu, WT; Bai, PY; Li, M; Ou, YJ; Li, F; Wang, LX; Wu, XH; Liu, JL; Xing, MY; Zhao, XM; Liu, H; Zhang, HB; Lyu, AK |
| Journal |
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY |
| Pub Year |
2022 |
| Type |
Article |
| Abstract |
Background: Macrophages are involved in the pathogenesis of pulmonary arterial hypertension (PAH). Caspase-8, an apical component of cell death pathways, is significantly upregulated in macrophages of PAH animal models. However, its role in PAH remains unclear. Caspase-8 plays a critical role in regulating inflammatory responses via inflammasome activation, cell death, and cytokine induction. This study investigated the mechanism of regulation of IL-1 beta (interleukin 1 beta) activation in macrophages by caspase-8. Methods: A hypoxia + SU5416-induced PAH mouse model and monocrotaline-induced rat model of PAH were constructed and the role of caspase-8 was analyzed. Results: Caspase-8 and cleaved-caspase-8 were significantly upregulated in the lung tissues of SU5416 and hypoxia-treated PAH mice and monocrotaline-treated rats. Pharmacological inhibition of caspase-8 alleviated PAH compared with wild-type mice, observed as a significant reduction in right ventricular systolic pressure, ratio of right ventricular wall to left ventricular wall plus ventricular septum, pulmonary vascular media thickness, and pulmonary vascular muscularization; caspase-8 ablated mice also showed significant remission. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cellss is closely associated with activation of the NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome and the IL-1 beta signaling pathway. Although caspase-8 did not affect extracellular matrix synthesis, it promoted inflammatory cell infiltration and pulmonary arterial smooth muscle cell proliferation via NLRP3/IL-1 beta activation during the development stage of PAH. Conclusions: Taken together, our study suggests that macrophage-derived IL-1 beta via caspase-8-dependent canonical inflammasome is required for macrophages to play a pathogenic role in pulmonary perivascular inflammation. |
| Issue |
42 |
| Volume |
42 |
