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.