IL-13 and IL-17A activate β1 integrin through an NF- kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle

• 成果类型: Article
• 署名作者: Ngo, Uyen; Shi, Ying; Woodruff, Prescott; Shokat, Kevan; Degrado, William; Jo, Hyunil; Sheppard, Dean; Sundaram, Aparna B.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11347
• DOI: 10.1073/pnas.2401251121
• 发表日期: 2024-08-20
• 关键词: phosphatidylinositol 4-phosphate 5-kinase; integrin activation; leukocyte adhesion; lfa-1 activation; extracellular-matrix; ferm domain; outside-in; kappa-b; asthma; rho

摘要

Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL- 13 and IL- 17A, activate type I and IL- 17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of beta 1 integrins detected by the conformation- specific antibody HUTS- 4. Moreover, HUTS- 4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease- relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the beta 1- activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide beta 1- CHAMP that forces an extended- open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine- induced activation of beta 1 integrins is regulated by a common pathway of NF-kappa B- mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1 gamma- mediated synthesis of PIP2 at focal adhesions, resulting in beta 1 integrin activation. Taken together, these data identify a pathway by which type I and IL- 17 cytokine receptor family stimulation induces functionally relevant beta 1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.