Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to β2-integrin dependent responses of equine neutrophils.
Abstract: Neutrophil infiltration is a prominent feature in a number of pathologic conditions affecting horses including recurrent airway obstruction, ischemia-reperfusion injury, and laminitis. Cell signaling components involved in neutrophil migration represent targets for novel anti-inflammatory therapies. In order to migrate into tissue, neutrophils must respond to chemoattractant signals in their external environment through activation of adhesion receptors (i.e. integrins) and reorganization of the actin cytoskeleton. Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS), a highly conserved actin-binding protein, has a well demonstrated role in cytoskeletal dependent cellular functions (i.e. adhesion, spreading, and migration), but the details of MARCKS involvement in these processes remain vague. We hypothesized that MARCKS serves as a link between the actin cytoskeleton and integrin function in neutrophils. Using a MARCKS-specific inhibitor peptide known as MANS on equine neutrophils in vitro, we demonstrate that inhibition of MARCKS function significantly attenuates β2-integrin-dependent neutrophil functions including migration, adhesion, and immune complex-mediated respiratory burst. The MANS peptide did not, however, inhibit the β2-integrin-independent PMA mediated respiratory burst. These results attest to the essential role of MARCKS function in regulating neutrophil responses, and strongly implicate MARCKS as a potential regulator of β2-integrins in neutrophils.
Copyright © 2014 Elsevier B.V. All rights reserved.
Publication Date: 2014-05-02 PubMed ID: 24857637PubMed Central: PMC4108539DOI: 10.1016/j.vetimm.2014.04.009Google Scholar: Lookup
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- Non-U.S. Gov't
Summary
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The research explores the key role of the protein MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) in the functioning of neutrophils—namely, migration, adhesion, and immune complex-related respiratory burst—in horses’ bodies. The findings suggest that its inhibition affects β2-integrin-dependent functionalities, highlighting MARCKS as a probable regulator of β2-integrins in neutrophils.
Importance of Neutrophils and The Role of MARCKS
- The research underlines the role of neutrophils, a type of white blood cell that is typically the first to respond to inflammation, in several pathologic conditions affecting horses, like recurrent airway obstruction, ischemia-reperfusion injury, and laminitis.
- Understanding the signaling components involved in the migration of neutrophils is crucial to forming potential anti-inflammatory treatments.
- The protein MARCKS is significant because it plays a big role in cytoskeleton-dependent cellular functions such as adhesion, spreading, and migration. However, its precise involvement in these processes hasn’t been clearly defined.
- The researchers posit that MARCKS could function as a connecting link between the actin cytoskeleton and integrin function in neutrophils.
Effect of Inhibiting MARCKS Function
- For the study, researchers used a MARCKS-specific inhibiting agent (the MANS peptide) on equine neutrophils in a lab setting.
- The results showed that when MARCKS function was inhibited, there was significant reduction in β2-integrin-dependent neutrophil functionalities, such as migration, adhesion, and immune complex-related respiratory burst.
- The MANS peptide did not, however, inhibit the β2-integrin-independent PMA mediated respiratory burst, shedding light on the specific and critical role of MARCKS in regulating β2-integrin-related neutrophil responses.
Implications of the Research
- These findings highlight the vital role of MARCKS in regulating neutrophil responses and suggest that it may serve as a potential regulator of β2-integrins in neutrophils.
- The research paves the way for further exploration into the role of MARCKS and how it can be used to develop novel anti-inflammatory therapies for conditions involving neutrophil infiltration in horses.
Cite This Article
APA
Sheats MK, Pescosolido KC, Hefner EM, Sung EJ, Adler KB, Jones SL.
(2014).
Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to β2-integrin dependent responses of equine neutrophils.
Vet Immunol Immunopathol, 160(3-4), 167-176.
https://doi.org/10.1016/j.vetimm.2014.04.009 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States; Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States. Electronic address: mkpeed@ncsu.edu.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States; Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
MeSH Terms
- Amino Acid Sequence
- Animals
- Antigen-Antibody Complex / physiology
- CD18 Antigens / immunology
- CD18 Antigens / physiology
- Cell Adhesion / drug effects
- Cell Adhesion / physiology
- Cell Movement / drug effects
- Cell Movement / physiology
- Conserved Sequence
- Horses / immunology
- Horses / physiology
- In Vitro Techniques
- Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
- Intracellular Signaling Peptides and Proteins / genetics
- Intracellular Signaling Peptides and Proteins / physiology
- Membrane Proteins / antagonists & inhibitors
- Membrane Proteins / genetics
- Membrane Proteins / physiology
- Molecular Sequence Data
- Myristoylated Alanine-Rich C Kinase Substrate
- Neutrophil Infiltration / drug effects
- Neutrophil Infiltration / immunology
- Neutrophil Infiltration / physiology
- Peptide Fragments / genetics
- Peptide Fragments / pharmacology
- Respiratory Burst / drug effects
- Sequence Homology, Amino Acid
- Tetradecanoylphorbol Acetate / pharmacology
Grant Funding
- R37 HL036982 / NHLBI NIH HHS
- T32 RR024394 / NCRR NIH HHS
- K01 OD015136 / NIH HHS
- R37 HL36982 / NHLBI NIH HHS
- T32 OD011130 / NIH HHS
- 5K01OD015136 / NIH HHS
- T35 OD011070 / NIH HHS
- T35 RR025837 / NCRR NIH HHS
Conflict of Interest Statement
. KBA holds 150,000 founders shares of a start-up biotech company, BioMarck, and serves as a scientific consultant and member of the scientific advisory board without monetary compensation. KBA receives over $100,000 yearly in research grants from National Institutes of Health (NIH) and U.S. Environmental Protection Agency. KBA is Editor-in-Chief of the American Journal of Respiratory Cell and Molecular Biology and receives a stipend of <$100,000 per year from the American Thoracic Society for this. The remaining authors have declared that no competing interests exist.
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Citations
This article has been cited 13 times.- 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.
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