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Effect of alternative CXCR2 ligands on human neutrophils in vitro

ABSTRACT: Targeting neutrophils has emerged as a promising therapeutic strategy for various inflammatory diseases. Here, we investigate a highly specific monoclonal antibody that targets CXCR2, which is a major chemokine receptor on neutrophils. This antibody functions as an inverse agonist, binds tightly to CXCR2 in a mutually exclusive manner versus IL-8, and completely blocks CXCR2-β-arrestin signaling and subsequent neutrophil functions. Treatment with the antibody appears to result in an overall reversal of IL-8 induced gene expressions in primary human neutrophils. The antibody demonstrates remarkable efficacy in controlling dysregulated neutrophil activity in peripheral circulation and inflammatory tissues in four inflammation animal models. In addition, administration of the antibody not only ameliorates the symptoms of neutrophilia, but also mitigates tissue damage in cases of acute lung inflammation and delayed-type-hypersensitivity reactions. We also checked the effects of the antibody on human neutrophils activated by the natural ligand IL-8 or not in vitro through RNAseq.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254095 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:[Background] TNFa-induced adipose-related protein (TIARP) is a six-transmembrane protein that is expressed on macrophages, neutrophils and synoviocytes. We have recently reported that TIARP deficient mice (TIARP-/-) spontaneously developed arthritis, and had the high susceptibility to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effect of TIARP to neutrophils and fibroblast-like syonoviocytes (FLS) has not been clearly elucidated. [Methods] We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/- mice. We characterized the differences of neutrophils between WT and TIARP-/- mice by DNA microarray. Transmigration assays of TIARP-/- neutrophils were performed in vitro and in vivo. FLS were cultured with TNF? and the production of CXCL2 (a specific ligand of CXCR1 and CXCR2) and IL-6 were measured by ELISA. Moreover, TIARP-/- mice transferred with K/BxN serum were treated with anti-IL-6R antibodies. [Results] Arthritis in TIARP-/- mice transferred with K/BxN serum was significantly exacerbated. We identified overexpression of CXCR1 and CXCR2 in TIARP-/- neutrophils by DNA microarray. Neutrophils from TIARP-/- mice showed strong migration activity. The enhancement of chomotactic activity of TIARP-/- neutrophil was greatly facilitated by CXCL2 in vitro and in vivo. In addition, TIARP-/-FLS has enhanced the production of CXCL2 and IL-6 and the cell proliferation in the presence of TNFa, and the blockade of IL-6R significantly attenuated arthritis in vivo. [Conclusion] Our findings indicate that TIARP might down-regulate the production of CXCL2 and IL-6 in FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, resulting in the protective ability of neutrophils migration into arthritic joints. Mice were treated with thiogycollate medium intraperitoneally. After 3 days, peritoneal macrophages were isolated from three WT or TIARP-deficient mice, and these cells were stimulated by TNF? for 24 hours. Ly6G+ Neutrophils were isolated from splenocytes by MACS.

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Effect of alternative CXCR2 ligands on human neutrophils in vitro

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