ABSTRACT
Studies in animal models suggest a linkage between inflammatory response to injury and subsequent nephron loss during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identifies the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD, and whole kidney RNA and protein analyses of mouse models of CKD, confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular (MPT) cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including TNFα and IL-1ß. Analyses of bulk RNA sequencing of TNFα-treated PCRCs or pseudo-bulk RNA sequencing of biopsies from the Kidney Precision Medicine Project (KPMP) datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacologic inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 (Myd88) and TIR-domain-containing adapter-inducing interferon-ß (Trif) suppressed TNFα- and IL-1ß-induced VCAM-1 expression in vitro. TNFα stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the MPT monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.
ABSTRACT
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by infiltration of inflammatory cells, hyperplasia of synovium, and destruction of the joint cartilage. Owing to the low drug delivery efficiency and limited immunosuppression effect, complete cure for RA remains a formidable challenge. Here, we show that live macrophages (Mφs) carrying protoporphyrin-loaded Fe3O4 nanoparticles can migrate to the RA tissues and inhibit the inflammation by sonodynamic therapy. The inflammation of RA leads to the release of cytokines, which guides the migration of the Mφs into the RA tissues, realizing precise delivery of therapeutics. The following sonodynamic therapy induced by ultrasound and protoporphyrin destructs the proliferating synovial cells and also infiltrated inflammatory cells, demonstrating significant therapeutic effect for RA. Meanwhile, the cytokines and relapse of RA can be remarkably suppressed because of the efficient damage to the resident inflammatory cells.