Dr. Reichner's lab focuses on mechanisms of tumor metastasis, macrophage biology and characterization of the b-glucan receptor during normal and septic conditions. Neutrophils are the most predominant innate immune cell in the circulation and are the first immune cells to respond to an injury or infection. Since most infections occur within bodily tissues, neutrophils must exit the bloodstream and precisely navigate to the infectious source to destroy the contaminating microbes and defend the health host.

Dr. Reichner’s lab studies the response of neutrophils to pathogenic fungi. The binding of neutrophils to fungi occurs by the cell surface receptor CR3 recognizing fungal beta-glucan which is a structural component of the cell wall of the pathogen. Since the anti-microbial function of neutrophils occurs within tissues, his lab considers the role of the extracellular matrix, tissue elasticity and the three dimensional microenvironment as regulatory factors mediating the response of the neutrophil. In sum, the neutrophil is sensitive to regulation by both receptor mediated biochemical interactions as well as the physical nature of the environment for which specific receptors are not readily apparent.

Biography

Dr. Jonathan Reichner is a Professor of Surgery in the Department of Surgery at Rhode Island Hospital and The Warren Alpert Medical School of Brown University.

He received his B.S. from Ohio State University in 1976 and worked as a clinical microbiologist until entering graduate school. He received his Ph.D. in Microbiology and Immunology from the State University of New York at Buffalo in 1983.  Dr. Reichner completed his postdoctoral training at the University of Connecticut Health Science Center, MD Anderson Hospital & Tumor Institute of the University of Texas Cancer Center, and the Johns Hopkins School of Medicine.  In 1988, he joined the Department of Medicine's Division of Hematology as an Assistant Professor of Medicine at Rhode Island Hospital and Brown University.  In 1991, he transferred to the Department of Surgery's Division of Surgical Research and was promoted to Associate Professor of Surgery in 1996. 

Dr. Reichner has been a member of the Pathobiology Graduate Faculty in the Department of Biology and Laboratory Medicine at Brown University since 1999. He was the Associate Director of the Pathobiology Graduate Program from 2003-2007.  He has been serving as the Interim Director since 2010 as well as Co-Director of the COBRE Center for Cancer Research Development at Rhode Island Hospital.  In 2014, Dr. Reichner was promoted to Professor of Surgery (Research) in the Department of Surgery.

Research Overview

Neutrophils as Tumor Killers

Neutrophils are the first line of defense against infection and exhibit a unique cell-killing mechanism called trogoptosis (“gnawing”), based on successive puncturing of cancer cell membranes. We investigate the efficacy of this mechanism in the context of different tumor cell surface markers as well as the extracellular matrix. We envision that neutrophil trogoptosis can be therapeutically enhanced for anti-tumor activity in combination with adjuvant drug therapy.

Neutrophil Mechanobiology

Inflammation is mediated by the neutrophil, a circulating white blood cell that is essential to eliminate infection, clear damaged tissue and initiate the return to health. In some diseases states inflammation becomes excessive and neutrophils cause damage to the organs they are designed to protect. Since human neutrophils cannot be studied while in the body, in vitro models are essential to understand how these cells behave. To mimic the physical nature of bodily tissues and organs, we apply different biomaterials to study neutrophils from healthy and critically ill patients as they act within the three dimensional space of an injured tissue. The long-term goal of our research is to control the activity of the cell to function optimally for the benefit of human health.

Neutrophils in the damage to vasculature endothelial cells during sepsis

Sepsis is a significant medical problem in the intensive care unit that occurs when a patient has a suspected source of infection and bodily injury which together drives the system-wide inflammatory system into hyperactivity. Neutrophils are the major inflammatory cells in the bloodstream and, when activated, can cause organ damage and can lead to death of the patient. We have identified a small fraction of all neutrophils cause most of this damage and we propose that they can be safely eliminated or blocked without causing suppression of the immune system.

Neutrophils in the Response to Fungal Pathogens

Infections with fungal pathogens can occur in patients while they are in an intensive care unit for a long period of time and are difficult to treat. Fungal pathogens are normally combated by the neutrophils in the immune system. The neutrophil response to fungi can be excessive and may cause tissue damage in excess of that needed to control the infection. This ongoing work is to test the possibility that neutrophil cell surface receptors called integrins can lessen the damaging response and maintain the protective immune response to fungi.

Research Statement

Neutrophils are capable of recognizing linear polymers of glucose linked in ß-1,3 conformation (viz., ß-glucan) which is a cell wall component of infectious microorganisms including yeast, fungi and bacteria. The recognition of ß-glucan by these cells is of benefit to host defense in two ways: first, since glucose does not occur in mature mammalian glycoproteins, ß-glucan provides a recognition mechanism through which neutrophils can bind and clear microorganisms without the need for opsonization; and second, ß-glucan binding stimulates neutrophil functions including chemotaxis, phagocytosis and oxidative burst. However, the mechanism(s) by which these inflammatory cells recognize ß-glucan is not defined. Work in this laboratory suggests that human neutrophils detect ß-glucan through novel interactions with cell surface integrins producing subsequent effects on cell motility. Ongoing efforts are directed at defining the mechanism(s) of this recognition and the second messenger signalling events that are triggered within the migrating cell. This work entails microscopic techniques in cell migration and immunocytochemistry, as well as protein biochemistry and molecular biology to investigate intracellular signalling pathways.

Funded Research

• 2023-2025: "Investigating the ability of human blood neutrophils to kill cancer"; R03 CA280714
• 2019-2023: "Identification of a damaging subset of neutrophils that arises in septic patients; RO1 HL147525
• 2014 –2020: “Neutrophil-Endothelial Interactions and Barrier Function in Sepsis”; R01 HL125265-01
• Multi-PI: M. Kim, J. Reichner, R. Waugh
• 2015-2020: “Use of Biomimicry to Determine the Effect of Sepsis on Neutrophil Traction”; R01-AI116629
• Multi-PI: J. Reichner and C. Franck

Scholarly Work

Johnson, C.M., O’Brien, X.M., Byrd, A.S., Parisi, V.E., Loosely, A.J., Li., W., Witt, H., Faridi, M.H., Lefort, C.T., Gupta, V., Kim, M., and Reichner, J.S. Integrin cross-talk regulates the human neutrophil response to fungal beta-glucan in the context of extracellular matrix: A prominent role for VLA3 in the anti-fungal response. J. Immunology 198:318-334, 2017

O’Brien, X.M., Biron, B.M. and Reichner, J.S. Consequences of extracellular trap formation in sepsis. Curr. Opin. Hemat., 24:66-71, 2017

Byrd, A.S., O’Brien, X.M., Laforce-Nesbitt, S.S., Parisi, V., Hirakawa, M.P., Bliss, J.M. and Reichner, J.S. NETosis in neonates: evidence of a ROS-independent pathway in response to fungal challenge. J. Infectious Diseases, 213:634-639, 2016.

Stout, D.A., Bar-Kochba, E., Estrada, J.B., Toyjanova, J., Kesari, H., Reichner, J.S. and Franck, C. Mean deformation metrics for quantifying 3D cell-matrix interactions in the absence of material properties. PNAS, 113:2898-2903, 2016. PMID: 26929377

Biron, B.M, Chung, C.S., O’Brien, X.M., Chen, Y., Reichner, J.S. and Ayala, A. Cl-amidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival, in a murine sepsis model. J. Innate Immunity, (epub ahead of press), 2016.

O’Brien, X.M. and Reichner, J.S. Neutrophil integrins and matrix ligands and NET release. Front. Immunol, 7:363-366, 2016.

Toyjanova, J., Flores, E., Reichner, J.S. and Franck, C. Matrix confinement plays a pivotal role in regulating neutrophil-generated tractions, speed and integrin utilization. J. Biol. Chem. 290:3752-3763, 2015.

Loosely, A., O’Brien, X., Reichner, J.S., and Tang, J.X. Describing Directional Cell Migration with a Characteristic Directionality Time. PLOS One, 10:e0127425, 2015

Ayala, A., Elphick, G.F., Kim, Y.S., Huang, X., Carreira-Rosario, A., Santos, S.C., Shubin, N.J., Chen Y., Reichner, J.S, Chung, C.S.Sepsis-Induced Potentiation of Peritoneal Macrophage Migration Is Mitigated by Programmed Cell Death Receptor-1 Gene Deficiency. J. Innate Immunity, 6:325-338, 2014.

O’Brien, X.M., Heflin, K.E., Loosley, A., Tang, J.X. and Reichner, J.S. Introducing a Novel Metric, Directionality Time, to Quantify Human Neutrophil Chemotaxis as a Function of Matrix Composition and Stiffness. J. Leuk. Biol, 95:993-1004, 2014.

Toyjanova, J., Bar-Kochba, E., Lopez-Fagundo, C., Reichner, J.S., Hoffman-Kim, D. and Franck, C. High resolution, large deformation traction force microscopy. PLOS One, 9:e90976, 2014.

Magruder, H.T, Quinn, J.A, Schwartzbauer, J.E., Reichner, J.S, Huang, A and Filardo, E.J. The G-protein-coupled estrogen receptor, GPER-1, promotes fibrillogenesis via a Shc-dependent pathway resulting in anchorage-independent growth. Hormones and Cancer 5:390-404, 2014.

Byrd, A.S., O'Brien, X.M., Johnson, C.M., Lavigne, L.M. and Reichner, J.S. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to C. albicans. J. Immunology 190:4136-4148, 2013.

Brancato, S.K., Thomay, A.A., Daley, J.M., Crane, M.J. Reichner, J.S., Sabo, E. and Albina, J.E. Toll-like receptor 4 signaling regulates the acute local inflammatory response to injury and the fibrosis/neovascularization of sterile wounds. Wound Repair Regen. 21: 2013.

Fox, E., Heffernan, D., Cioffi, W., and Reichner, J.S. Neutrophils from critically ill patients mediate profound loss of barrier integrity. Critical Care. 17:226-232, 2013.

O'Brien XM, Heflin KE, Lavigne LM, Yu K, Kim M, Salomon AR, Reichner JS. Lectin site ligation of CR3 induces conformational changes and signaling. J Biol Chem. 287:3337-3348, 2012

Newsome CT, Flores E, Ayala A, Gregory S, Reichner J.S. Improved antimicrobial host defense in mice following poly-(1,6)-β-D-glucopyranosyl-(1,3)-β-D-glucopyranose glucan treatment by a gender-dependent immune mechanism. Clin Vaccine Immunol. 18:2043-9, 2011

Daley, J.M., Brancato, S.K., Thomay, A.A., Reichner, J.S. and Albina, J.E. The phenotype of the wound macrophage. J. Leuk. Biol. 87:1, 2010.

Oakes, P.W., Morin, N.A., Zitterbart, D.P., Patel, D. C., Fabry, B., Reichner, J.S. (Corresponding author), and Tang J.X. Neutrophil morphology and migration are affected by substrate elasticity. Blood, 114:1387-1395, 2009.

Elphick, G.F., Sarangi, P.P., Hyun, Y-M, Hollenbaugh, J.A., Ayala, A., Biffl, W.L., Chung, H-L., Rezaie, A.R., McGrath, J.L., Topham, D.J., Reichner, J.S. and Kim, M. Recombinant human activated protein C inhibits integrin-mediated neutrophil function. Blood, 113:4078-4085

Muratore, C.S., Luks, F.I., Zhou, Y., Harty, M., Reichner, J., and Tracy, T.F. Endotoxin alters early fetal lung morphogenesis. J. Surg. Res. 155:225-230, 2009.

Morin NA, Oakes PW, Hyun YM, Lee D, Chin YE, King MR, Springer TA, Shimaoka M, Tang JX, Reichner JS, Kim M. Abstract Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med. 2008 Jan 21;205(1):195-205.

Lavigne LM, O'Brien XM, Kim M, Janowski JW, Albina JE, Reichner JS. Integrin engagement mediates the human polymorphonuclear leukocyte response to a fungal pathogen-associated molecular pattern. J Immunol. 2007 Jun 1;178(11):7276-82.

LeBlanc, B.W., Albina, J.E. and Reichner, J.S. Effect of beta-glucan on neutrophil chemotaxis in vivo. Journal Leukocyte Biol. 79:667-675, 2006.

Lavigne LM, Albina JE, Reichner JS. beta-Glucan Is a Fungal Determinant for Adhesion-Dependent Human Neutrophil Functions. J Immunol. 177:8667-75, 2006.

Daley, J.M., Reichner, J.S., Mahoney, E.J., Manfield, L., Henry Jr., W.L., Mastrofrancesco, B., and Albina, J.E. The anti-inflammatory neutrophil: Wound neutrophils suppress macrophage TNF-alpha release. J. Immunol. 174:2265-2272, 2005.

Albina, J.E., Mahoney, E.J., Daley, J.M., Wesche, D.E, Morris, S.M., and Reichner, J.S. Macrophage arginase I regulation by C/EBPß. SHOCK 23:168-172, 2005.

Tsikitis, V., Morin, N., Harrington, E., Albina, J.E. and Reichner, J.S. Glucan protects the integrity of an endothelial monolayer in the presence of activated neutrophils. J. Immunol. 173:1284-1291, 2004.

Tsikitis, V.L., Albina, J.E., and Reichner, J.S. ß-glucan affects leukocyte navigation in complex chemotactic gradients. Surgery 136:384-389, 2004.

Ivanov, S.S., Chung, A.S., Yuan, P.Z., Guan, A.Y., Sachs, K.V., Reichner, J.S. and Chin, Y.E. Antibodies immobilized as arrays to profile protein post-translational modifications in mammalian cells. Molecular and Cellular Proteomics 3:788-795, 2004