title: 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.
authors.affiliation: 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.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Sheats
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Pescosolido
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Hefner
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
authors.forename: Eui Jae
authors.initials: EJ
authors.lastname: Sung
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, United States.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Adler
authors.affiliation: 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.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D017124:Conserved Sequence; D006736:Horses / Q000276:immunology / Q000502:physiology*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000936:Antigen-Antibody Complex; D018821:CD18 Antigens; D047908:Intracellular Signaling Peptides and Proteins; C483227:MARCKS-related peptide; D008565:Membrane Proteins; D010446:Peptide Fragments; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D013755:Tetradecanoylphorbol Acetate
keywords: Adhesion; Beta2-integrin; Inflammation; Migration; Neutrophil; Respiratory burst