Tissue plasminogen activator activates NF-κB through a pathway involving annexin A2/CD11b and integrin-linked kinase

Ling Lin, Chuanyue Wu, Kebin Hu

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1329-1338
Number of pages10
JournalJournal of the American Society of Nephrology
Volume23
Issue number8
DOIs
StatePublished - Aug 2012

All Science Journal Classification (ASJC) codes

  • Nephrology

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