p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration

Eckert, Rachael E.; Sharief, Yousuf; Jones, Samuel L.

doi:10.1016/j.vetimm.2008.11.007

Cited by 20 publications

(23 citation statements)

References 89 publications

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“…Therefore, it was worthwhile to test whether p38 inhibitors could exert some inhibitory effects on acrolein-induced inflammatory processes in vivo. Numerous recent studies indicate that SB203580, a specific p38 inhibitor, has potentials to suppress neutrophil influx and migration in models of acute lung injury [17,26,27]. In the mouse model established here by subchronic acrolein exposure, we found that SB203580 significantly reduced the accumulation of neutrophils and macrophages in the BALF, suppressed TNF-α and KC release in both the BALF and lung tissue, and attenuated inflammatory cell infiltration and goblet cell hyperplasia in the airways.…”

Section: Discussionsupporting

confidence: 52%

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

Liu

Wang

Han

et al. 2009

International Immunopharmacology

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Section: Discussionsupporting

confidence: 52%

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

Liu

Wang

Han

et al. 2009

International Immunopharmacology

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“…We provided direct and specific experimental verification that phosphorylation of endothelial LSP1 is blunted by pharmacological inhibition of p38 MAPK. It is documented that inhibition of p38 MAPK signaling downregulates the expression of ␤ 2 -integrins (45) and decreases leukocyte adhesion to endothelial cells (12,16,39,42). In light of these results, LSP1 phosphorylation in endothelial cells could be diminished as a result of decreased neutrophil adhesion to endothelial cells.…”

Section: Resultsmentioning

confidence: 99%

ICAM-1-mediated leukocyte adhesion is critical for the activation of endothelial LSP1

Hossain

Qadri

et al. 2013

American Journal of Physiology-Cell Physiology

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Leukocyte-endothelial interaction triggers signaling events in endothelial cells prior to transendothelial migration of leukocytes. Leukocyte-specific protein 1 (LSP1), expressed in endothelial cells, plays a pivotal role in regulating subsequent recruitment steps following leukocyte adhesion. In neutrophils, LSP1 is activated by phosphorylation of its serine residues by molecules downstream of p38 MAPK and PKC. Whether leukocyte adhesion to endothelial cells is required for endothelial LSP1 activation remains elusive. In addition, discrepancies in the functions of endothelial and leukocyte LSP1 in leukocyte adhesion prevail. We demonstrate that adhesion of wild-type ( Lsp1+/+) neutrophils to LSP1-deficient ( Lsp1−/−) endothelial cells was significantly reduced compared with adhesion to Lsp1+/+ endothelial cells. Immunoblotting revealed increased phosphorylated endothelial LSP1 in the presence of adherent Lsp1−/− neutrophils [stimulated by macrophage inflammatory protein-2 (CXCL2), TNF-α, or thapsigargin], but not cytokine or chemokine alone. Pharmacological inhibition of p38 MAPK by SB-203580 (10 μM) significantly blunted the phosphorylation of endothelial LSP1. Functionally blocking endothelial ICAM-1 or neutrophil β2-integrins diminished neutrophil adhesion and phosphorylation of endothelial LSP1. The engagement of endothelial ICAM-1 cross-linking, which mimics leukocyte adhesion, resulted in phosphorylation of endothelial LSP1. In neutrophil-depleted Lsp1+/+ mice, administration of ICAM-1 cross-linking antibody resulted in increased phosphorylation of LSP1 and p38 MAPK in TNF-α-stimulated cremaster muscle. In conclusion, endothelial LSP1 participates in leukocyte adhesion in vitro, and leukocyte adhesion through ICAM-1 fosters the activation of endothelial LSP1, an effect at least partially mediated by the activation of p38 MAPK. Endothelial LSP1, in contrast to neutrophil LSP1, is not phosphorylated by cytokine or chemokine stimulation alone.

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“…42 Furthermore, parallel PtdIns(3,4,5)P 3 -independent mechanisms, such as the p38 MAPK pathway, add additional complexity to the signaling events regulating directional migration in neutrophils. 43 We propose a model in which active PTEN would normally negatively contribute to regulation of directional sensing by blocking the development/ maintenance of the PtdIns(3,4,5)P 3 gradient at the leading edge. PTEN therefore acts as the "brake" to PI3K's "accelerator" role.…”

Section: Discussionmentioning

confidence: 99%

Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop

Kuiper

Sun

Magalhães

et al. 2011

Blood

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IntroductionNeutrophils are important mediators of the innate immune system and are rapidly recruited from the circulation to sites of infection to eliminate pathogenic threats. Key to this recruitment is the release of chemoattractants by infected host tissue or pathogens, which subsequently form a chemical gradient that attracts neutrophils to the appropriate sites. 1 In response to a chemotactic gradient, neutrophils polarize and form a leading edge pointing toward the chemoattractant source and a posterior structure called the uropod. Actin polymerization within the leading edge drives up-gradient protrusion, whereas myosin activity in the uropod detaches the rear of the cell. The proper coordination of these polarized events is essential for directional migration and depends on the asymmetrical distribution of specific molecular determinants. A hallmark of neutrophil polarization is the asymmetrical accumulation of the phospholipid phosphatidylinositol(3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] in the leading edge. 2,3 The formation of PtdIns(3,4,5)P 3 is catalyzed by PI3Ks and is counteracted by the activity of the lipid phosphatases phosphatase and tensin homolog (PTEN) and SH2-containing inositol phosphatase (SHIP), which generate the lipid products PtdIns(4,5)P 2 and PtdIns(3,4)P 2 , respectively. 4,5 Several studies have suggested that the establishment of a robust PtdIns(3,4,5)P 3 levels requires a positive feedback loop, and this is corroborated by the observation that the introduction of exogenous PtdIns(3,4,5)P 3 induces further accumulation of endogenous PtdIns(3,4,5)P 3 in a Rho GTPase-dependent fashion. 6,7 Rac and actin polymerization were both shown to be required for the establishment of PtdIns(3,4,5)P 3 polarization via a feedback loop mechanism. 8,9 However, the exact mechanism remains elusive. Because neutrophils produce reactive oxygen species (ROS) within the leading edge during chemotaxis, 10,11 and the activity of the lipid phosphatase PTEN is markedly reduced by ROS, 12,13 we hypothesized that local ROS production in neutrophils could regulate PtdIns(3,4,5)P 3 levels through redox regulation of PTEN. We indeed identified PTEN to be a major target of chemoattractantinduced ROS formation and demonstrate that its enzymatic activity decreases accordingly. Decreased PTEN activity led to an increase of PtdIns(3,4,5)P 3 , which could be reversed by ROS scavengers or genetic ablation of NADPH-oxidase 2 (NOX2). Consistent with this finding, reduction of ROS inhibited directional migration of neutrophils toward N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), uncapping of actin filaments, and Rac activity. Although Rac GTPases are important downstream effectors of PtdIns(3,4,5)P 3 , they are also crucial for ROS production. Rescue experiments with small GTPase Rac effector mutants revealed that Rac facilitates PtdIns(3,4,5)P 3 accumulation and that this effect depends on its ability to activate NADPH-oxidase. Methods Abs and reagentsRabbit polyclonal Ab against phosphorylated AKT (Thr308; #2...

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p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration

Cited by 20 publications

References 89 publications

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog

ICAM-1-mediated leukocyte adhesion is critical for the activation of endothelial LSP1

Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop

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