Caspase-8 Promotes Pulmonary Hypertension by Activating Macrophage-Associated Inflammation and IL-1β (Interleukin 1β) Production.

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-1β (interleukin 1β) 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-1β 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-1β activation during the development stage of PAH.

CONCLUSIONS:

Taken together, our study suggests that macrophage-derived IL-1β via caspase-8-dependent canonical inflammasome is required for macrophages to play a pathogenic role in pulmonary perivascular inflammation.

• Authors: Wuwei Rong, Chenchen Liu, Xiaoming Li, Naifu Wan, Lijiang Wei, Wentong Zhu, Peiyuan Bai, Ming Li, Yangjing Ou, Fang Li, Lingxia Wang, Xuanhui Wu, Jianling Liu, Mingyan Xing, Xiaoming Zhao, Han Liu, Haibing Zhang, Ankang Lyu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 42 Issue 5 Pg. 613-631 (05 2022) ISSN: 1524-4636 [Electronic] United States
• PMID: 35387479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Monocrotaline
• Caspase 8
• Caspase 1

Topics

• Animals
• Caspase 1 (metabolism)
• Caspase 8 (metabolism)
• Hypertension, Pulmonary (chemically induced, drug therapy, genetics)
• Hypoxia (complications)
• Inflammasomes (metabolism)
• Inflammation (complications)
• Interleukin-1beta (metabolism)
• Macrophages (metabolism)
• Mice
• Monocrotaline (toxicity)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Rats