p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration.
Abstract: Equine laminar tissues do not contain resident neutrophils and have less superoxide dismutase (SOD) activity than other equine tissues, which makes them inherently more vulnerable to damage induced by reactive oxygen species (ROS) produced by neutrophils that enter the tissues. In the advanced clinical stages of acute laminitis, pathologic events in affected feet include a breakdown in the basement membrane, neutrophil infiltration, and platelet-neutrophil aggregates in laminar dermal veins, highlighting the contribution of neutrophils to the pathophysiology of the disease. The aim of this study was to determine the role of p38 MAPK in the mechanism underlying equine neutrophil migration to potentially reveal therapeutic targets that may limit lamellar damage from the neutrophil influx that occurs in acute laminitis. We determined that the endogenous chemoattractant LTB(4) transiently activated p38 MAPK and induced chemotaxis of equine primary neutrophils. Inhibition with the p38 MAPK specific inhibitor SB203580 reduced LTB(4)-induced migration in a dose-dependent manner with an IC(50) of 2.8 microM. We then examined the potential mechanisms underlying the ability of SB203580 to abolish migration. We determined that inhibition of p38 MAPK with 10 microM SB203580 disrupted the ability of neutrophils to polarize in response to LTB(4) and PAF. In contrast, p38 MAPK did not appear to be required for chemoattractant- or PKC-induced beta2 integrin-dependent adhesion or chemoattractant-induced upregulation of surface beta2 integrins, but was required for TNFalpha-induced adhesion. These findings support a function for p38 MAPK in equine neutrophil migration and suggest the potential for the ability of p38 MAPK inhibition to limit neutrophilic inflammation in the laminae during acute laminitis.
Publication Date: 2008-11-07 PubMed ID: 19095309DOI: 10.1016/j.vetimm.2008.11.007Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research article studies the role of p38 mitogen-activated kinase (MAPK) in the migration of equine neutrophils, highlighting its potential as a therapeutic target for laminitis, a disease typically characterized by infiltration of neutrophils.
Overview of Research
- The study investigates the role of p38 mitogen-activated kinase (MAPK) in the migration of equine (horse) neutrophils – a type of white blood cell that is critical in the body’s immune response, specifically the body’s defense against bacterial infections.
- This investigation is significant given that, in horses, there’s a condition known as laminitis – a severe inflammatory condition of the laminae, the soft tissue structures that attach the coffin bone of a horse’s foot to the hoof wall – which can be debilitating. One of the features of this disease is an increased number of infiltrating neutrophils.
Research Findings
- The researchers found that a biochemical called LTB(4) activates p38 MAPK, and in turn prompts chemotaxis, meaning it moves equine neutrophils. Chemotaxis is an immune response that causes cells to move towards areas where they are needed, often sites of infection or inflammation.
- When p38 MAPK was inhibited using the specific inhibitor SB203580, the neutrophils’ migration was reduced. The ability for this inhibitor to reduce the number of infiltrating neutrophils suggests it could potentially be used therapeutically to manage conditions like laminitis, where there’s a notable presence of these cells.
- The study also examined how the inhibitor was able to stop migration. It was found that inhibition of p38 MAPK disrupted the ability of neutrophils to polarize – a process necessary for movement – in response to LTB(4) and another molecule, PAF. Importantly, p38 MAPK did not seem to be required for adhesion – the sticking of cells to each other or to surfaces – induced by chemoattractant or PKC, except when the process was induced by TNFalpha, another inflammatory substance.
Conclusion
- The findings suggest that p38 MAPK plays a significant role in the migration of equine neutrophils and, therefore, has potential to be a key target for limiting inflammation in conditions like acute laminitis.
Cite This Article
APA
Eckert RE, Sharief Y, Jones SL.
(2008).
p38 mitogen-activated kinase (MAPK) is essential for equine neutrophil migration.
Vet Immunol Immunopathol, 129(3-4), 181-191.
https://doi.org/10.1016/j.vetimm.2008.11.007 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, United States.
MeSH Terms
- Animals
- CD18 Antigens / metabolism
- Cell Adhesion
- Cells, Cultured
- Chemotaxis, Leukocyte / physiology
- Dose-Response Relationship, Drug
- Enzyme Inhibitors / pharmacology
- Gene Expression Regulation / physiology
- Horses / physiology
- Imidazoles / pharmacology
- Inflammation / metabolism
- Leukotriene B4 / metabolism
- Neutrophils / metabolism
- Pyridines / pharmacology
- p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
- p38 Mitogen-Activated Protein Kinases / metabolism
Citations
This article has been cited 5 times.- Yang H, Zhang H, Tian L, Guo P, Liu S, Chen H, Sun L. Curcumin attenuates lupus nephritis by inhibiting neutrophil migration via PI3K/AKT/NF-κB signalling pathway. Lupus Sci Med 2024 Jul 24;11(2).
- Conley H, Till RL, Berglund AK, Jones SL, Sheats MK. A myristoylated alanine-rich C-kinase substrate (MARCKS) inhibitor peptide attenuates neutrophil outside-in β(2)-integrin activation and signaling. Cell Adh Migr 2023 Dec;17(1):1-16.
- Bayless RL, Sheats MK, Jones SL. Withaferin A Inhibits Neutrophil Adhesion, Migration, and Respiratory Burst and Promotes Timely Neutrophil Apoptosis. Front Vet Sci 2022;9:900453.
- Martin EM, Till RL, Sheats MK, Jones SL. Misoprostol Inhibits Equine Neutrophil Adhesion, Migration, and Respiratory Burst in an In Vitro Model of Inflammation. Front Vet Sci 2017;4:159.
- Xu N, Hossain M, Liu L. Pharmacological inhibition of p38 mitogen-activated protein kinases affects KC/CXCL1-induced intraluminal crawling, transendothelial migration, and chemotaxis of neutrophils in vivo. Mediators Inflamm 2013;2013:290565.
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