Tissue Plasminogen Activator Activates NF-κB through a Pathway Involving Annexin A2/CD11b and Integrin-Linked Kinase

• Published in: Journal of the American Society of Nephrology Vol. 23; no. 8; pp. 1329 - 1338
• Main Authors: Lin, Ling, Wu, Chuanyue, Hu, Kebin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.08.2012
• Subjects: Animals; Annexin A2 - metabolism; Basic Research; Biological and medical sciences; CD11b Antigen - metabolism; Kidneys; Macrophages - metabolism; Medical sciences; Mice; Mice, Knockout; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction; Tissue Plasminogen Activator - metabolism; Urinary system involvement in other diseases. Miscellaneous; Kidney disease; Nephrology; Urinary system disease; Serine endopeptidases; Annexin II; Enzyme; Pathogenesis; Rodentia; Chronic kidney disease; Urology; t-Plasminogen activator; Peptidases; Signal transduction; Vertebrata; Mammalia; Nephropathy; Mouse; Animal; Renal failure; Hydrolases; Transcription factor NFκB
• DOI: 10.1681/ASN.2011111123
• ISSN: 1046-6673

NF-κB activation is central to the initiation and progression of inflammation, which contributes to the pathogenesis of CKD. Tissue plasminogen activator (tPA) modulates the NF-κB pathway, but the underlying mechanism remains unknown. We investigated the role of tPA signaling in macrophage NF-κB activation and found that tPA activated NF-κB in a time- and dose-dependent manner. tPA also induced the expression of the NF-κB-dependent chemokines IP-10 and MIP-1α. The protease-independent action of tPA required its membrane receptor, annexin A2. tPA induced the aggregation and interaction of annexin A2 with integrin CD11b, and ablation of CD11b or administration of anti-CD11b neutralizing antibody abolished the effect of tPA. Knockdown of the downstream effector of CD11b, integrin-linked kinase, or disruption of its engagement with CD11b also blocked tPA-induced NF-κB signaling. In vivo, tPA-knockout mice had reduced NF-κB signaling, fewer renal macrophages, and less collagen deposition than their counterparts. Taken together, these data suggest that tPA activates the NF-κB pathway in macrophages through a signaling pathway involving annexin A2/CD11b-mediated integrin-linked kinase.