Critical role of neutrophil alkaline phosphatase in the antimicrobial function of neutrophils

Li, Haining; Zhao, Yao; Li, Wei; Yang, Jin; Wu, Han

doi:10.1016/j.lfs.2016.06.005

Cited by 18 publications

(14 citation statements)

References 24 publications

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“…Hence, the results of this study are in line with the suggestion that AP may exert a role in neutrophil-mediated pulmonary inflammation. In vitro, neutrophils increase AP expression in response to inflammatory stimuli, which is associated with enhanced chemotaxis, increased production of reactive oxygen species, and effective induction of apoptosis [17]. Also, several studies have shown increased AP expression by neutrophils in case of inflammation, for example in patients with bacterial infections [25][26][27] and chronic inflammatory conditions such as obesity [28].…”

Section: Discussionmentioning

confidence: 99%

“…AP has been detected in lung tissue, though its exact origin remains unclear. Alveolar type II cells have been suggested as a potential source of AP [14,15], but also neutrophils may exert a role due to the presence of AP in their secretory vesicles [16,17]. The exact role and effects of AP in pulmonary inflammation is uncertain.…”

Section: Introductionmentioning

confidence: 99%

“…Treatment with AP yielded so far conflicting results on the pulmonary inflammatory response. One preclinical study showed administration of AP to increase the risk of developing acute lung injury [18], whereas another study suggests a protective role of AP in pulmonary inflammation [17].…”

Section: Introductionmentioning

confidence: 99%

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Alkaline phosphatase in pulmonary inflammation—a translational study in ventilated critically ill patients and rats

Juschten

Ingelse

Bos

et al. 2020

ICMx

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Background Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. Aim To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats Methods AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. Results BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14–1.20] vs 0.55 [0.21–1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18–3.59] vs 1.01 [0.80–1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. Conclusions In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alkaline phosphatase in pulmonary inflammation—a translational study in ventilated critically ill patients and rats

Juschten

Ingelse

Bos

et al. 2020

ICMx

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“…The immune imbalance can lead to lessened cytokine production and reduced T cell proliferation 44,45 . TNAP is expressed on immune cells, including neutrophils and T lymphocytes, where it plays a role in B cell differentiation, so it is often upregulated at the site of inflammation 46–49 . TNAP has also been shown to modulate T cell function in a heterozygous TNAP+/− mouse model of colitis 50 .…”

Section: Discussionmentioning

confidence: 99%

Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

Brichacek

Benkovic

Chakraborty

et al. 2019

Sci Rep

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Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis.

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“…ALPL gene in neutrophils encodes neutrophil alkaline phosphatase (NAP) 27 , which is a membrane bounding glycosylated protein 28 with its function of catalyzing dephospharylation and transphosphorylation reactions 29 . During bacterial infections, when the cells encounter stimulations of inflammatory signals, neutrophil NAP number dramatically increases and NAP-over-expressed neutrophils display enhanced chemotaxis, which promote its migration into inflammatory sites, ROS generation and apoptosis 30 . The role of NAP in chronic inflammation has not been explored.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of a Novel Neutrophil Activation Marker Associated with Obesity

Pan

Choi

Shi

et al. 2019

Sci Rep

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Obesity is accompanied by low-grade systemic inflammation that etiologically contributes to obesity-induced cardiovascular disease (CVD). Growing evidence supports that neutrophil, the most abundant type of leukocytes in human, is most likely to be the target peripheral leukocyte subtype initiating the inflammatory cascade in obesity. However, few studies have systematically assessed the genome wide changes in neutrophils associated with obesity. In this study, a hypothesis-free OMIC approach (i.e. the discovery phase) and a target approach (i.e. the validation phase) were used to identify obesity related neutrophil activation markers and their roles on CVD risks. In the discovery phase, genome wide DNA methylation, RNA-sequencing and quantitative proteomics were obtained from purified neutrophils (12 obese vs . 12 lean). In the validation phase, gene expression levels of the promising genes from the OMIC platforms were measured in 81 obese cases vs . 83 lean controls, and the association between the expression levels and CVD risks were evaluated. Significant difference was found for one gene, alkaline phosphatase, liver/bone/kidney ( ALPL ), across 3 OMIC platforms. In the validation phase, the gene expression levels of ALPL in leukocytes were significantly higher in obese compared with lean subjects (p < 0.05). Within the obese population, we observed that ALPL expression level showed significantly positive association with CVD risk factors (p < 0.05) including systolic blood pressure, diastolic blood pressure, mean arterial pressure, carotid intima–media thickness and borderline significance with fasting insulin (p = 0.08). This study identified one novel marker ALPL of neutrophil activation in response to obesity and provided evidence that obesity induced change in ALPL expression was associated with CVD risk factors.

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Critical role of neutrophil alkaline phosphatase in the antimicrobial function of neutrophils

Cited by 18 publications

References 24 publications

Alkaline phosphatase in pulmonary inflammation—a translational study in ventilated critically ill patients and rats

Alkaline phosphatase in pulmonary inflammation—a translational study in ventilated critically ill patients and rats

Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

Discovery and Validation of a Novel Neutrophil Activation Marker Associated with Obesity

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