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Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices.

ABSTRACT: Neutrophil trafficking in tissues critically regulates the body's immune response. Neutrophil migration can either play a protective role in host defense or cause health problems. Fibroblast growth factor 23 (FGF23) is a known biomarker for chronic kidney disease (CKD) and was recently shown to impair neutrophil arrest on endothelium and transendothelial migration. In the present study, we further examined the effect of FGF23 on human blood neutrophil chemotaxis using two new microfluidic devices. Our results showed that chemotaxis of FGF23 pre-treated neutrophils to a fMLP gradient, in the presence or absence of a uniform FGF23 background, is quantitatively lower compared to the control cells. This effect is accompanied with a stronger drifting of FGF23 pre-treated cells along the flow. However, without the FGF23 pre-treatment, the FGF23 background only reduces chemotaxis of transmigrated cells through the thin barrier channel to the fMLP gradient. The effect of FGF23 on neutrophil migration and the correlation between multiple cell migration parameters are further revealed by chemotactic entropy and principle component analysis. Collectively, these results revealed the effect of FGF23 on weakening neutrophil chemotaxis, which shed light on FGF23 mediated neutrophil migration with direct disease relevance such as CKD.

SUBMITTER: Yang K

PROVIDER: S-EPMC5465076 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices.

Yang Ke K Peretz-Soroka Hagit H Wu Jiandong J Zhu Ling L Cui Xueling X Zhang Michael M Rigatto Claudio C Liu Yong Y Lin Francis F

Scientific reports 20170608 1

Neutrophil trafficking in tissues critically regulates the body's immune response. Neutrophil migration can either play a protective role in host defense or cause health problems. Fibroblast growth factor 23 (FGF23) is a known biomarker for chronic kidney disease (CKD) and was recently shown to impair neutrophil arrest on endothelium and transendothelial migration. In the present study, we further examined the effect of FGF23 on human blood neutrophil chemotaxis using two new microfluidic device ...[more]

PMID: 28596573

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Project description:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25-dihydroxy-vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1-fibroblast growth factor receptor 1 (FN1-FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1-FGFR1 proteins, the effectiveness of infigratinib, a FGFR1-3 tyrosine kinase inhibitor, was studied in an open-label, single-center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)-DOTATATE and 18Fluoride (18F)-Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment-related, dose-limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher-than-expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment-related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life-limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Dataset Information

Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices.

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Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices.

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