Modulation of infection‐mediated migration of neutrophils and CXCR2 trafficking by osteopontin

Abstract

SummaryOsteopontin (OPN) is a pro-inflammatory protein that paradoxically protects against inflammation and bone destruction in a mouse model of endodontic infection. Here we have tested the hypothesis that this effect of OPN is mediated by effects on migration of innate immune cells to the site of infection. Using the air pouch as a model of endodontic infection in mice, we showed that neutrophil accumulation at the site of infection with a mixture of endodontic pathogens is significantly reduced in OPNdeficient mice. Reduced neutrophil accumulation in the absence of OPN was accompanied by an increase in bacterial load. OPN-deficiency did not affect neutrophil survival, CXCR2 ligand expression, or the production of inflammatory cytokines in the air pouch. In vitro, OPN enhanced neutrophil migration to CXCL1, whereas in vivo, inhibition of CXCR2 suppressed cellular infiltration in air pouches of infected wild-type mice by > 50%, but had no effect in OPN-deficient mice. OPN increased cell surface expression of CXCR2 on bone marrow neutrophils in an integrina v -dependent manner, and suppressed the internalization of CXCR2 in the absence of ligand. Together, these results support a model where the protective effect of OPN results from enhanced initial neutrophil accumulation at sites of infection resulting in optimal bacterial killing. We describe a novel mechanism for this effect of OPN: integrin-a v -dependent suppression of CXCR2 internalization in neutrophils, which increases the ability of these cells to migrate to sites of infection in response to CXCR2 ligands.

Serum osteopontin negatively impacts on intima‐media thickness in patients with systemic lupus erythematosus

“…OPN is constitutively expressed by macrophages/foam cells and sustains pro‐inflammatory environment within atherosclerotic plaque by exerting an autocrine/paracrine activity . Specifically, OPN contributes to macrophage chemotaxis, activation, survival and pro‐inflammatory M1 polarization, in addition to promote neutrophil recruitment and activation . As an additional mechanism, OPN has been demonstrated to regulate interferon‐I response, which has a role in both pathophysiology of SLE and subclinical atherosclerosis .…”

“…31 Specifically, OPN contributes to macrophage chemotaxis, activation, survival and pro-inflammatory M1 polarization, in addition to promote neutrophil recruitment and activation. 13,32 As an additional mechanism, OPN has been demonstrated to regulate interferon-I response, which has a role in both pathophysiology of SLE and subclinical atherosclerosis. 33,34 Despite highly speculative, available data indicate OPN not only as an innocent biomarker, but rather an active mediator of plaque vulnerability.…”

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

“…As the peroxidase enzyme converts chloride and hydrogen peroxide into hypochlorous acid during the respiratory burst phase, MPO measured by bioluminescence imaging and colorimetric activity assay is used by the neutrophil to kill fungi and other pathogens. Singh et al 9 found that reduced neutrophil accumulation in the absence of OPN was accompanied by an increase in bacterial load. Barreno et al 30 also found that following O 3 exposure, bronchoalveolar lavage fluid neutrophil levels were significantly reduced in OPN-deficient mice compared with wild-type mice.…”

“…7 OPN, encoded by the secreted phosphoprotein 1 (SPP1) gene, is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, where it acts as an immune modulator in a variety of ways. [8][9][10][11] First, OPN has chemotactic properties that promote cell recruitment to inflammatory sites. 12,13 It also functions as an adhesion protein involved in cell attachment and wound healing.…”

Anti-inflammatory, anti-oxidative stress and novel therapeutic targets for cholestatic liver injury

“…Osteopontin (OPN) is a recently discovered molecule that has chemotactic effects on neutrophils during cholestasis (21). OPN is a pleiotropic protein that can play different roles in different cells (22).…”