Monocytes augment inflammatory responses in human aortic valve interstitial cells via β2-integrin/ICAM-1-mediated signaling

作者：Luo, Zichao; The, Erlinda; Zhang, Peijian; Zhai, Yufeng; Yao, Qingzhou; Ao, Lihua; Zeng, Qingchun^*; Fullerton, David A.; Meng, Xianzhong^*

来源：Inflammation Research, 2022, 71(5-6): 681-694.

DOI：10.1007/s00011-022-01566-2

• Aortic valves
• Inflammation
• Adhesion molecules
• Monocytes
• YAP

Objective Inflammatory infiltration in aortic valves promotes calcific aortic valve disease (CAVD) progression. While soluble extracellular matrix (ECM) proteins induce inflammatory responses in aortic valve interstitial cells (AVICs), the impact of monocytes on AVIC inflammatory responses is unknown. We tested the hypothesis that monocytes enhance AVIC inflammatory responses to soluble ECM protein in this study. Methods Human AVICs isolated from normal aortic valves were cocultured with monocytes and stimulated with soluble ECM protein (matrilin-2). ICAM-1 and IL-6 productions were assessed. YAP and NF-kappa B phosphorylation were analyzed. Recombinant CD18, neutralizing antibodies against beta(2)-integrin or ICAM-1, and inhibitor of YAP or NF-kappa B were applied. Results AVIC expression of ICAM-1 and IL-6 was markedly enhanced by the presence of monocytes, although matrilin-2 did not affect monocyte production of ICAM-1 or IL-6. Matrilin-2 up-regulated the expression of monocyte beta(2)-integrin and AVIC ICAM-1, leading to monocyte-AVIC adhesion. Neutralizing beta(2)-integrin or ICAM-1 in coculture suppressed monocyte adhesion to AVICs and the expression of ICAM-1 and IL-6. Recombinant CD18 enhanced the matrilin-2-induced ICAM-1 and IL-6 expression in AVIC monoculture. Further, stimulation of coculture with matrilin-2 induced greater YAP and NF-kappa B phosphorylation. Inhibiting either YAP or NF-kappa B markedly suppressed the inflammatory response to matrilin-2 in coculture. Conclusion Monocyte beta(2)-integrin interacts with AVIC ICAM-1 to augment AVIC inflammatory responses to soluble matrilin-2 through enhancing the activation of YAP and NF-kappa B signaling pathways. Infiltrated monocytes may promote valvular inflammation through cell-cell interaction with AVICs to enhance their sensitivity to damage-associated molecular patterns.

• 单位
  南方医科大学