The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

Kumar, Sachin; Xu, Juying; Kumar, Ravi; Lakshmikanthan, Sribalaji; Kapur, Reuben; Kofron, Matthew; Chrzanowska‐Wodnicka, Magdalena; Filippi, Marie Dominique

doi:10.1084/jem.20131706

Cited by 55 publications

(60 citation statements)

References 63 publications

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“…The serine/threonine kinase that phosphorylates Shp1 on Ser591 is unknown but it may be regulated by other signaling molecules involved in neutrophil activation. A recently published study suggests that the GTPase Rap1b is involved in the regulation of Shp1 activity (34). Kumar et al (34), found that stimulation of wild type neutrophils with fMLP induced Shp1 activation, whereas Shp1 activation was reduced in Rap1b −/− neutrophils, suggesting that Rap1b either directly, or more likely indirectly through affects on serine kinases, modulates Shp1 activity.…”

Section: Discussionmentioning

confidence: 99%

“…A recently published study suggests that the GTPase Rap1b is involved in the regulation of Shp1 activity (34). Kumar et al (34), found that stimulation of wild type neutrophils with fMLP induced Shp1 activation, whereas Shp1 activation was reduced in Rap1b −/− neutrophils, suggesting that Rap1b either directly, or more likely indirectly through affects on serine kinases, modulates Shp1 activity. As the phosphorylation state of different signaling molecules and integrin activity in unstimulated Shp1-deficient neutrophils and wild type neutrophils is similar, Shp1 is a phosphatase exclusively regulating cell function in stimulated neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…This speculation is supported by the fact that Akt phosphorylation, a readout for PI3K activation, is increased and PtdIns (4,5)P 2 levels in these cells are elevated. The fact that either under activation of the Akt pathway (in PI3K deficient cells) or over activation of the pathway (in Shp1 deficient cells) leads to defective leukocyte recruitment suggests that PtdIns (4,5)P 2 ,-PI3K-PtdIns (3,4,5)P 3 –Akt- signaling pathways have to be tightly regulated to ensure balance of signaling to allow both the adhesion and de-adhesion steps required for leukocyte recruitment into inflamed tissue (17, 34). …”

Section: Discussionmentioning

confidence: 99%

“…and the cremaster muscle was prepared for intravital imaging as previously described (6, 31, 33). Some mice were pretreated with either PBS or the Shp-1/2 inhibitor NSC87877 (0.15 mg/mouse i.p., EMD Millipore, Darmstadt, Germany) prior the TNF-α injection (34). Measurements were performed in postcapillary venules with a diameter between 20–40 µm.…”

Section: Methodsmentioning

confidence: 99%

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Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment

Stadtmann

Block

Volmering

et al. 2015

The Journal of Immunology

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Neutrophil recruitment to site of inflammation plays a pivotal role in host defense. However, an overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of αLβ2 (LFA-1), which can be induced by rolling on E-selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Shp1 show increased leukocyte adhesion, but interpretation of these data is limited by the severe global phenotype of these mice. Here, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling and transendothelial migration in vitro and in vivo. Shp1 deficiency results in an increased neutrophil adhesion in vivo. However, neutrophil crawling, transmigration and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIγ-activity and thereby modulates PtdIns(4,5)P2 levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment

Stadtmann

Block

Volmering

et al. 2015

The Journal of Immunology

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“…Subsequently, Akt phosphorylation at threonine 308 and serine 473 takes place through mechanisms involving PI3K activation [60]. This pathway of Akt activation promotes neutrophil accumulation in LPS-treated lungs[61], and is implicated in the susceptibility of COPD patients to influenza[62] and in the activated PI3K-δ syndrome characterized by repeated respiratory infections[63]. …”

Section: The Role Of Cell Ca2+mentioning

confidence: 99%

Macrophage-epithelial interactions in pulmonary alveoli

Bhattacharya

Westphalen

2016

Semin Immunopathol

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Alveolar macrophages have been investigated for years by approaches involving macrophage extraction from the lung by bronchoalveolar lavage, or by cell removal from lung tissue. Since extracted macrophages are studied outside their natural milieu, there is little understanding of the extent to which alveolar macrophages interact with the epithelium, or with one another to generate the lung’s innate immune response to pathogen challenge. Here, we review new evidence of macrophage-epithelial interactions in the lung and we address the emerging understanding that the alveolar epithelium plays an important role in orchestrating the macrophage driven immune response.

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Integrated miRNA and mRNA expression profiling reveals dysregulated miRNA‐mRNA regulatory networks in eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps

Wang

Luan

et al. 2021

Int Forum Allergy Rhinol

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Background: The precise mechanisms underlying pathogenesis of different subtypes of chronic rhinosinusitis with nasal polyps (CRSwNP) are still unclear.Emerging evidence indicates that microRNAs may play a role in the pathogenesis of CRSwNP. This study aimed to identify the dysregulated microRNA-messenger RNA (miRNA-mRNA) regulatory networks in eosinophilic (E) and noneosinophilic (non-E) CRSwNP. Methods: Whole-transcriptome sequencing was performed on nasal tissues of patients with ECRSwNP and non-ECRSwNP, and control subjects. An integrated analysis of miRNA and mRNA expression was conducted to identify key mRNAs and miRNAs involved in the pathogenesis of ECRSwNP and non-ECRSwNP. The miRNAs of interest and their target genes were validated using quantitative realtime polymerase chain reaction (PCR). Results: A group of differentially expressed mRNAs (DE-mRNAs) and miR-NAs (DE-miRs) were identified in ECRSwNP patients vs control subjects, non-ECRSwNP patients vs control subjects, and non-ECRSwNP vs ECRSwNP patients, respectively. Pathway enrichment analysis showed distinct immune and inflammatory functions associated with DE-mRNAs and target genes of DE-miRs in ECRSwNP vs control and non-ECRSwNP vs control groups. The miRNA-mRNA regulatory networks constructed with Cytoscape highlighted the roles of miR-154, miR-221, and miR-223 family miRNAs relating to both ECRSwNP and non-ECRSwNP, and the roles of the let-7 and miR-34/449 families in the development of non-ECRSwNP. Assessment using real-time PCR for the expression of miRNAs and target genes demonstrated highly consistent data with the RNA sequencing data. Conclusion: ECRSwNP and non-ECRSwNP patients express distinct miRNA-mRNA regulatory networks compared with control subjects, thus providing

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The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

Abstract: Mice lacking the small GTPase Rap1b exhibit enhanced neutrophil recruitment to inflamed lungs and susceptibility to endotoxin shock via enhance PI3K-Akt activation.

Cited by 55 publications

References 63 publications

Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment

Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment

Macrophage-epithelial interactions in pulmonary alveoli

Integrated miRNA and mRNA expression profiling reveals dysregulated miRNA‐mRNA regulatory networks in eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps

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