Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils

Liu, Wenli; Liu, Yueqin; Li, Hongzhen; Rodgers, Griffin P.

doi:10.1152/ajpcell.00336.2017

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…Previous studies evaluating the role of OLFM4 in murine neutrophils have been under the assumption that all neutrophils express OLFM4 protein. 21,22,34,35 Furthermore, these studies were done on the C57Bl6 background, which we show here to only express OLFM4 in 6-8% of neutrophils. This perhaps suggests that some of the observed phenotype differences, such as differences in superoxide production and increased killing of bacteria, may be due to secreted OLFM4 rather than the intrinsically expressed OLFM4, because differences reported would be attributable to only 6-8% of neutrophils.…”

Section: Discussionmentioning

confidence: 87%

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Olfactomedin 4 marks a subset of neutrophils in mice

et al. 2018

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Neutrophils are the most abundant immune cell of the innate immune system and participate in essential immune functions. Heterogeneity within neutrophils has been documented, but it is difficult to distinguish if these are altered activation states of a single population or separate subpopulations of neutrophils determined at the time of differentiation. Several groups have identified a subset of human neutrophils that express olfactomedin 4 (OLFM4) and increased OLFM4+ neutrophils during sepsis is correlated with worse outcome, suggesting these neutrophils or the OLFM4 they secrete may be pathogenic. We tested if mice could be used as a model to study OLFM4+ neutrophils. We found the OLFM4 expressing subset of neutrophils is conserved in mice. Depending on the strain, 7% to 35% of murine neutrophils express OLFM4 and expression is determined early in neutrophil differentiation. OLFM4+ neutrophils phagocytose and transmigrate with similar efficiency as OLFM4- neutrophils. Here we show that OLFM4+ and OLFM4- neutrophils undergo NETosis and OLFM4 colocalizes within NETs. Finally, we generated an OLFM4 null mouse and show that these mice are protected from death when challenged with sepsis, providing further evidence that the OLFM4 expressing subpopulation of neutrophils, or the OLFM4 they secrete, may be pathogenic during overwhelming infection.

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Section: Discussionmentioning

confidence: 87%

“…Previous studies evaluating the role of OLFM4 in murine neutrophils have been under the assumption that all neutrophils express OLFM4 protein (21, 22, 34, 35). Furthermore, these studies were done on the C57Bl6 background, which we show here to only express OLFM4 in 6–8% of neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Olfactomedin 4 marks a subset of neutrophils in mice

et al. 2018

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“…Studies in mice have shown OLFM4 to potentially play a role in down-regulation of the innate immune response in murine Helicobacter pylori infection by inhibiting cathepsin G (13)(14)(15). Another study showed that OLFM4 may be involved in superoxide production to augment neutrophil apoptosis (26). However, these studies were carried out assuming that all neutrophils expressed OLFM4, whereas the finding that only a subset of murine neutrophils express OLFM4 was only recently published (12).…”

Section: Discussionmentioning

confidence: 99%

The olfactomedin‐4 positive neutrophil has a role in murine intestinal ischemia/reperfusion injury

et al. 2019

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Olfactomedin-4 (OLFM4) identifies a subset of neutrophils conserved in both mouse and man, associated with worse outcomes in several inflammatory conditions. We investigated the role of OLFM4-positive neutrophils in murine intestinal ischemia/reperfusion (IR) injury. Wild-type (WT) C57Bl/6 and OLFM4 null mice were subjected to intestinal IR injury and then monitored for survival or tissues harvested for further analyses. In vivo intestinal barrier function was determined via functional assay of permeability to FITC-dextran. OLFM4 null mice had a significant 7-d survival benefit and less intestinal barrier dysfunction compared with WT. Early after IR, WT mice had worse mucosal damage on histologic examination. Experiments involving adoptive transfer of bone marrow demonstrated that the mortality phenotype associated with OLFM4-positive neutrophils was transferrable to OLFM4 null mice. After IR injury, WT mice also had increased intestinal tissue activation of NFkB and expression of iNOS, 2 signaling pathways previously demonstrated to be involved in intestinal IR injury. In combination, these experiments show that OLFM4-positive neutrophils are centrally involved in the pathologic pathway leading to intestinal damage and mortality after IR injury. This may provide a therapeutic target for mitigation of intestinal IR injury in a variety of common clinical situations.

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“…OLFM4 gene expression in the whole blood was upregulated in septic patients with acute respiratory distress syndrome [ 53 ]. OLFM4 contributed to H 2 O 2 -induced NADPH oxidase activation and cellular apoptosis in mouse neutrophils [ 54 ]. Conversely, the contradictory results of OLFM4 on inflammation have been reported in several studies.…”

Section: Discussionmentioning

confidence: 99%

Qinbaohong Zhike Oral Liquid Attenuates LPS-Induced Acute Lung Injury in Immature Rats by Inhibiting OLFM4

Zhang

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Acute respiratory infections (ARIs) are a common public safety threat with high morbidity and mortality in pediatric patients worldwide. Qinbaohong Zhike oral liquid (QBH), a marketed traditional Chinese medicine product, has been widely used to cure respiratory diseases. QBH is reported to have antitussive, expectorant, and antiasthmatic properties. However, its treatment effect against ARIs is not elucidated. This study aimed to explore the therapeutic efficacy of QBH in the treatment of ARIs-induced pneumonia. Network pharmacology was used to predict the possible targets of QBH against ARIs. Next, the tracheal lipopolysaccharide (LPS-)-induced acute lung injury (ALI) immature rat model was constructed to evaluate the therapeutic effect of QBH. Tandem mass tag (TMT-)-based quantitative proteomics was then used to screen the in-depth disease targets of QBH. QBH exerted a protective effect against LPS-induced ALI by inhibiting pulmonary pathological damage. QBH also reduced the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and granulocyte macrophage colony-stimulating factor (GM-CSF) in the serum and IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF in the lung tissue. Based on proteomic data, olfactomedin 4 (OLFM4) related to immunity and inflammation was selected as a potential target. Western blot analysis further confirmed the moderating effect of QBH downregulation on OLFM4 in the lung tissue. Our findings demonstrated that QBH alleviated lung tissue damage and inflammatory reaction via inhibiting OLFM4 expression in LPS-challenged immature rats. Our research indicates that QBH may have therapeutic potential for treating ARIs-related ALI in pediatric patients, which also serves as a candidate target for drug therapy of ALI by intervening OLFM-related signaling pathways.

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Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils

Cited by 14 publications

References 32 publications

Olfactomedin 4 marks a subset of neutrophils in mice

Olfactomedin 4 marks a subset of neutrophils in mice

The olfactomedin‐4 positive neutrophil has a role in murine intestinal ischemia/reperfusion injury

Qinbaohong Zhike Oral Liquid Attenuates LPS-Induced Acute Lung Injury in Immature Rats by Inhibiting OLFM4

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