Aaron C. Petrey, PhD
- Departments: Pathology - Assistant Professor
- Divisions: Microbiology and Immunology
My research focuses on platelets and megakaryocytes as effector cells capable of mediating inflammation through interactions with immune and non-immune cells. These studies focus on the extracellular matrix glycosaminoglycan hyaluronan (HA) as a key molecule that modulates innate immune mechanisms which when dysregulated can lead to disease. My work recently uncovered a novel mechanism in inflammatory bowel disease (IBD) whereby platelet interactions with HA regulate immune cell recruitment and inflammation in the intestinal microvasculature. Using mouse models, biochemical assays, tissue and primary cells from IBD patients, these studies provide evidence that platelet hyaluronidase-2 regulates the early stages of disease progression by degradation of a unique form of HA present on the surface of the inflamed intestinal microvasculature. Unexpectedly, this pathway becomes dysregulated in IBD patients and in murine models of colitis.
Under normal physiological conditions, a dynamic, glycan-rich matrix comprised of HA and other glycoconjugates lines the vascular endothelium and restricts inflammatory cell access. However, in the context of tissue damage or infection, HA may become covalently modified with the heavy chains (HC) of serum inter-α-inhibitor to form a biologically distinct HA-HC complex that can be observed as “cable-like” structures. This novel pathological form of HA is pro-inflammatory, highly adhesive for naïve leukocytes and platelets, and functions as a unique damage-associated molecular pattern at the interface of inflammation and coagulation. My research seeks to understand how this novel matrix is regulated, how HA-HC controls leukocyte and platelet responses, define the receptor(s) that mediate recognition and activation, and determine the signaling pathways regulated by HA-HC.
Altered platelet function is a hallmark of many inflammatory sates, and my work examines the hypothesis that in chronic inflammatory disease states, such as in IBD, platelets (and other hematopoietic cells) are ‘born’ dysregulated due to alterations within the bone marrow microenvironment which lead to dysregulation of protective mechanisms and acquisition of pro-inflammatory features. My research provides evidence that HA-HC accumulates within the bone marrow during inflammation and contributes to altered megakaryocyte and myeloid development. These preliminary studies have led to the identification a HA receptor with previously unknown roles regulating hematopoiesis and inflammation.
- Petrey AC, Obery DR, Kessler SP PhD, Zawerton A, Flamion B, de la Motte CA (2019). Platelet Hyaluronidase-2 regulates the early stages of inflammatory disease in colitis. (Epub ahead of print) Blood.
- Petrey AC, de la Motte CA (2018). Hyaluronan in inflammatory bowel disease: Cross-linking inflammation and coagulation. Matrix Biol, 78-79, 314-323.
- Kessler SP, Obery DR, Nickerson KP, Petrey AC, McDonald C, de la Motte CA (2018). Multifunctional Role of 35 Kilodalton Hyaluronan in Promoting Defense of the Intestinal Epithelium. J Histochem Cytochem, 66(4), 273-287.
- Kim Y, West GA, Ray G, Kessler SP, Petrey AC, Fiocchi C, McDonald C, Longworth MS, Nagy LE, de la Motte CA (2017). Layilin is critical for mediating hyaluronan 35kDa-induced intestinal epithelial tight junction protein ZO-1 in vitro and in vivo. Matrix Biol, 66, 93-109.
- Petrey AC, de la Motte CA (2017). The extracellular matrix in IBD: a dynamic mediator of inflammation. Curr Opin Gastroenterol, 33(4), 234-238.
- Petrey AC, de la Motte CA (2016). Thrombin Cleavage of Inter-α-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix. J Biol Chem, 291(47), 24324-24334.
- Flanagan-Steet H, Matheny C, Petrey A, Parker J, Steet R (2016). Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology. Biochim Biophys Acta, 1860(9), 1845-53.
- Petrey AC, Obery DR, Kessler SP, Flamion B, de la Motte CA (2016). Hyaluronan Depolymerization by Megakaryocyte Hyaluronidase-2 Is Required for Thrombopoiesis. Am J Pathol, 186(9), 2390-403.
- Flanagan-Steet H, Aarnio M, Kwan B, Guihard P, Petrey A, Haskins M, Blanchard F, Steet R (2015). Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting. J Bone Miner Res, 31(3), 535-48.
- Petrey AC, de la Motte CA (2014). Hyaluronan, a crucial regulator of inflammation. Front Immunol, 5, 101.
- Petrey AC, Flanagan-Steet H, Johnson S, Fan X, De la Rosa M, Haskins ME, Nairn AV, Moremen KW, Steet R (2011). Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II. Dis. Models Mech, 5(2), 177-90.