Joel M Linden

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Primary Appointment

Professor, Medicine

Education

  • BS, Applied Mathematics/Biology, Brown University
  • PhD, Pharmacology, University of Virginia

Research Disciplines

Cancer Biology, Immunology, Molecular Physiology and Biological Physics, Translational Science

Research Interests

Adenosine receptor signaling

Research Description

The focus of my research has been the pharmacology and physiology of adenosine receptors. Various agonists and antagonists of adenosine receptors have therapeutic uses or potential for the treatment of cardiovascular diseases, inflammation, tissue transplantation, cancer, and diabetes.

Personal Statement

The focus of my research has been characterization of adenosine signaling by four G protein coupled receptors (A1, A2A, A2B and A3). My laboratory has characterized adenosine receptor subtypes by synthesizing novel agonist and antagonist radioligands, photoaffinity probes and anti-receptor antibodies. We have prepared cell lines that express the eight recombinant human and mouse adenosine receptor subtypes. We participated in the early cloning of adenosine receptors, the construction and characterization of receptor chimera and mutants, production and purification of epitope-tagged A1, A2A and A2B adenosine receptors and purification of receptor-G protein complexes. We have made several global and conditional adenosine receptor knock-out mice. An Established Investigator Award from the American Heart Association supported my early work.
In the mid 1990's the focus of my work shifted to anti-inflammatory effects of A2A receptors on immune cells. We found that activation of A2A receptors inhibited ischemia-reperfusion injury in almost all tissues. Adenosine acts primarily on A2A receptors on iNKT cells to reduce the initiation of an inflammatory cascade - thereby identifying the iNKT cell as an important mediator of innate tissue injury. We have ongoing studies on the use of A2AR agonists to improve the outcome of tissue transplantation. In collaboration with UVa chemist Dr. Timothy Macdonald we characterized novel A2AR agonists. This work was the basis for Adenosine Therapeutics, founded in 1999 and sold in 2008.
I spent 10 years, from 2009-2020 at the La Jolla Institute of Immunology studying the effects of A2A signaling in immune cells and patients with sickle cell anemia and the effects of A2A and A2B antagonists for cancer immunotherapy. Recently we found that A2B receptor blockade has beneficial effects in type 2 diabetes and we are investigating new treatments based on novel A2B blockers, being developed at a new start up company, Adenomed.

Selected Publications

2022

Dolina, J. S., Lee, J., Moore, E. L., Hope, J. L., Gracias, D. T., Matsutani, T., . . . Schoenberger, S. P. (2022). Developmentally distinct CD4+ Treg lineages shape the CD8+ T cell response to acute Listeria infection. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119(10). doi:10.1073/pnas.2113329119

2021

Wang, L., Londono, L. M., Cowell, J., Saatci, O., Aras, M., Ersan, P. G., . . . Cekic, C. (2021). Targeting Adenosine with Adenosine Deaminase 2 to Inhibit Growth of Solid Tumors.. Cancer research, 81(12), 3319-3332. doi:10.1158/0008-5472.can-21-0340

2020

Dhanwani, R., Takahashi, M., Mathews, I. T., Lenzi, C., Romanov, A., Watrous, J. D., . . . Sharma, S. (2020). Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response. SCIENCE ADVANCES, 6(30). doi:10.1126/sciadv.aba3688

Chen, S., Akdemir, I., Fan, J., Linden, J., Zhang, B., & Cekic, C. (2020). The Expression of Adenosine A2B Receptor on Antigen-Presenting Cells Suppresses CD8+ T-cell Responses and Promotes Tumor Growth. CANCER IMMUNOLOGY RESEARCH, 8(8), 1064-1074. doi:10.1158/2326-6066.CIR-19-0833

2019

Lindner, J. R., Belcik, T., Widlansky, M., Harmann, L. M., Karafin, M. S., Wandersee, N. J., . . . Field, J. J. (2019). Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease. PLOS ONE, 14(7). doi:10.1371/journal.pone.0218783

2018

Franco, A., Kumar, J., Lin, G., Behnamfar, N., Hsieh, L. -E., Shimizu, C., . . . Linden, J. (2018). Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to Fc and adenosine. EUROPEAN JOURNAL OF IMMUNOLOGY, 48(3), 482-491. doi:10.1002/eji.201747139

Yu, J. C., Lin, G., Field, J. J., & Linden, J. (2018). Induction of antiinflammatory purinergic signaling in activated human iNKT cells. JCI INSIGHT, 3(17). doi:10.1172/jci.insight.91954

2017

Young, A., Ngiow, S. F., Gao, Y., Patch, A. -M., Barkauskas, D. S., Messaoudene, M., . . . Smyth, M. J. (2018). A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment. CANCER RESEARCH, 78(4), 1003-1016. doi:10.1158/0008-5472.CAN-17-2826

Davidson, B. P., Belcik, J. T., Landry, G., Linden, J., & Lindner, J. R. (2017). Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease. ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES, 34(8), 1187-1194. doi:10.1111/echo.13601

Belcik, J. T., Davidson, B. P., Xie, A., Wu, M. D., Yadava, M., Qi, Y., . . . Lindner, J. R. (2017). Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling. CIRCULATION, 135(13), 1240-1252. doi:10.1161/CIRCULATIONAHA.116.024826

Acuff, N. V., & Linden, J. (2017). Using Visualization of t-Distributed Stochastic Neighbor Embedding To Identify Immune Cell Subsets in Mouse Tumors. JOURNAL OF IMMUNOLOGY, 198(11), 4539-4546. doi:10.4049/jimmunol.1602077

Field, J. J., Majerus, E., Gordeuk, V. R., Gowhari, M., Hoppe, C., Heeney, M. M., . . . Nathan, D. G. (2017). Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. BLOOD ADVANCES, 1(20), 1645-1649. doi:10.1182/bloodadvances.2017009613

2016

Cekic, C., & Linden, J. (2016). Purinergic regulation of the immune system. NATURE REVIEWS IMMUNOLOGY, 16(3), 177-192. doi:10.1038/nri.2016.4

Pei, H., & Linden, J. (2016). Adenosine influences myeloid cells to inhibit aeroallergen sensitization. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 310(10), L985-L992. doi:10.1152/ajplung.00330.2015

Linden, J. (2016). Optimizing radiation for cancer immunotherapy. TRANSLATIONAL CANCER RESEARCH, 5(2), 191-193. doi:10.21037/tcr.2016.01.10

2015

Nayak, S., Khan, M. A. H., Wan, T. C., Pei, H., Linden, J., Dwinell, M. R., . . . Auchampach, J. A. (2015). Characterization of Dahl salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension. PURINERGIC SIGNALLING, 11(4), 519-531. doi:10.1007/s11302-015-9470-7

Wu, M. D., Belcik, J. T., Qi, Y., Zhao, Y., Benner, C., Pei, H., . . . Lindner, J. R. (2015). Abnormal Regulation of Microvascular Tone in a Murine Model of Sickle Cell Disease Assessed by Contrast Ultrasound. JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY, 28(9), 1122-1128. doi:10.1016/j.echo.2015.05.012

Belcik, J. T., Mott, B. H., Xie, A., Zhao, Y., Kim, S., Lindner, N. J., . . . Lindner, J. R. (2015). Augmentation of Limb Perfusion and Reversal of Tissue Ischemia Produced by Ultrasound-Mediated Microbubble Cavitation. Circulation-Cardiovascular Imaging, 8(4). doi:10.1161/CIRCIMAGING.114.002979

Beech, J., Saleh, L., Frentzel, J., Figler, H., Corrêa, I. R., Baker, B., . . . Kelly, K. A. (2015). Multivalent site-specific phage modification enhances the binding affinity of receptor ligands.. Bioconjugate chemistry, 26(3), 529-536. doi:10.1021/acs.bioconjchem.5b00011

Beech, J., Saleh, L., Frentzel, J., Figler, H., Correa, I. R. J., Baker, B., . . . Kelly, K. A. (2015). Multivalent Site-Specific Phage Modification Enhances the Binding Affinity of Receptor Ligands. BIOCONJUGATE CHEMISTRY, 26(3), 529-536. doi:10.1021/acs.bioconjchem.5b00011

Tian, Y., Marshall, M., French, B. A., Linden, J., & Yang, Z. (2015). The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A2A receptors. BASIC RESEARCH IN CARDIOLOGY, 110(2). doi:10.1007/s00395-015-0473-x

2014

Field, J. J., Nathan, D. G., & Linden, J. (2014). The Role of Adenosine Signaling in Sickle Cell Therapeutics. HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA, 28(2), 287-+. doi:10.1016/j.hoc.2013.11.003

Linden, J. M., Koepple, M., Elder, D., & Gibson, A. G. (2014). Fracture mechanics of crack propagation in composite repairs of steel pressure piping. JOURNAL OF REINFORCED PLASTICS AND COMPOSITES, 33(6), 526-532. doi:10.1177/0731684413500366

Tian, Y., Linden, J., French, B. A., & Yang, Z. (2014). Atorvastatin at Reperfusion Reduces Myocardial Infarct Size in Mice by Activating eNOS in Bone Marrow-Derived Cells. PLOS ONE, 9(12). doi:10.1371/journal.pone.0114375

2013

Kennedy, D. P., McRobb, F. M., Leonhardt, S. A., Purdy, M., Figler, H., Marshall, M. A., . . . Yeager, M. (2014). The Second Extracellular Loop of the Adenosine A1 Receptor Mediates Activity of Allosteric Enhancers. MOLECULAR PHARMACOLOGY, 85(2), 301-309. doi:10.1124/mol.113.088682

Field, J. J., Lin, G., Okam, M. M., Majerus, E., Keefer, J., Onyekwere, O., . . . Nathan, D. G. (2013). Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson. BLOOD, 121(17), 3329-3334. doi:10.1182/blood-2012-11-465963

Linden, J. (2013). Adenosine Promotes Tumor Metastasis. SCIENCE SIGNALING, 6(277). doi:10.1126/scisignal.2004290

Lin, G., Field, J. J., Yu, J. C., Ken, R., Neuberg, D., Nathan, D. G., & Linden, J. (2013). NF-κB Is Activated in CD4+ iNKT Cells by Sickle Cell Disease and Mediates Rapid Induction of Adenosine A2A Receptors. PLOS ONE, 8(10). doi:10.1371/journal.pone.0074664

Harris, D. A., Zhao, Y., LaPar, D. J., Emaminia, A., Steidle, J. F., Stoler, M., . . . Lau, C. L. (2013). Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model. JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 145(3), 854-861. doi:10.1016/j.jtcvs.2012.03.079

2012

Li, Y., Figler, R. A., Kolling, G., Bracken, T. C., Rieger, J., Stevenson, R. W., . . . Warren, C. A. (2012). Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment. BMC INFECTIOUS DISEASES, 12. doi:10.1186/1471-2334-12-342

Chhabra, P., Linden, J., Lobo, P., Okusa, M. D., & Brayman, K. L. (2012). The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation. CURRENT DIABETES REVIEWS, 8(6), 419-433. doi:10.2174/157339912803529878

Li, L., Huang, L., Ye, H., Song, S. P., Bajwa, A., Lee, S. J., . . . Okusa, M. D. (2012). Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. JOURNAL OF CLINICAL INVESTIGATION, 122(11), 3931-3942. doi:10.1172/JCI63170

Barletta, K. E., Cagnina, R. E., Burdick, M. D., Linden, J., & Mehrad, B. (2012). Adenosine A2B Receptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 186(10), 1044-1050. doi:10.1164/rccm.201204-0622OC

Linden, J. (2012). Role of Adenosine in Response to Vascular Inflammation. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 32(4), 843-844. doi:10.1161/ATVBAHA.112.247874

Linden, J. (2012). TRANSLATIONAL MEDICINE Longer life for artificial joints. NATURE, 487(7406), 179-180. doi:10.1038/487179a

Linden, J. (2012). Statins Counter the Effects of Hyperlipidemia on iNKT Cells Editorial to: "Statin-Induced Immunomodulation Alters Peripheral Invariant Natural Killer T-Cell Prevalence in Hyperlipidemic Patients" by E. Nakou et al.. CARDIOVASCULAR DRUGS AND THERAPY, 26(4), 277-279. doi:10.1007/s10557-012-6391-3

Warren, C. A., Calabrese, G. M., Li, Y., Pawlowski, S. W., Figler, R. A., Rieger, J., . . . Guerrant, R. L. (2012). Effects of adenosine A2A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice. BMC INFECTIOUS DISEASES, 12. doi:10.1186/1471-2334-12-13

Warren, C. A., Li, Y., Calabrese, G. M., Freire, R. S., Zaja-Milatovic, S., van Opstal, E., . . . Guerrant, R. L. (2012). Contribution of Adenosine A2B Receptors in Clostridium difficile Intoxication and Infection. INFECTION AND IMMUNITY, 80(12), 4463-4473. doi:10.1128/IAI.00782-12

Field, J. J., Burdick, M. D., DeBaun, M. R., Strieter, B. A., Liu, L., Mehrad, B., . . . Strieter, R. M. (2012). The Role of Fibrocytes in Sickle Cell Lung Disease. PLOS ONE, 7(3). doi:10.1371/journal.pone.0033702

2011

Cekic, C., Sag, D., Li, Y., Theodorescu, D., Strieter, R. M., & Linden, J. (2012). Adenosine A2B Receptor Blockade Slows Growth of Bladder and Breast Tumors. JOURNAL OF IMMUNOLOGY, 188(1), 198-205. doi:10.4049/jimmunol.1101845

Emaminia, A., LaPar, D. J., Zhao, Y., Steidle, J. F., Harris, D. A., Laubach, V. E., . . . Lau, C. L. (2011). Adenosine A2A Agonist Improves Lung Function During Ex Vivo Lung Perfusion. ANNALS OF THORACIC SURGERY, 92(5), 1840-1846. doi:10.1016/j.athoracsur.2011.06.062

Barletta, K. E., Cagnina, R. E., Wallace, K. L., Ramos, S. I., Mehrad, B., & Linden, J. (2012). Leukocyte compartments in the mouse lung: Distinguishing between marginated, interstitial, and alveolar cells in response to injury. JOURNAL OF IMMUNOLOGICAL METHODS, 375(1-2), 100-110. doi:10.1016/j.jim.2011.09.013

Field, J. J., Nathan, D. G., & Linden, J. (2011). Targeting iNKT cells for the treatment of sickle cell disease. CLINICAL IMMUNOLOGY, 140(2), 177-183. doi:10.1016/j.clim.2011.03.002

Fredholm, B. B., IJzerman, A. P., Jacobson, K. A., Linden, J., & Mueller, C. E. (2011). International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors-An Update. PHARMACOLOGICAL REVIEWS, 63(1), 1-34. doi:10.1124/pr.110.003285

Wilson, J. M., Kurtz, C. C., Black, S. G., Ross, W. G., Alam, M. S., Linden, J., & Ernst, P. B. (2011). The A2B Adenosine Receptor Promotes Th17 Differentiation via Stimulation of Dendritic Cell IL-6. JOURNAL OF IMMUNOLOGY, 186(12), 6746-6752. doi:10.4049/jimmunol.1100117

Figler, R. A., Wang, G., Srinivasan, S., Jung, D. Y., Zhang, Z., Pankow, J. S., . . . Linden, J. (2011). Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans. DIABETES, 60(2), 669-679. doi:10.2337/db10-1070

2010

Zhao, Y., LaPar, D. J., Steidle, J., Emaminia, A., Kron, I. L., Ailawadi, G., . . . Lau, C. L. (2010). Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 29(12), 1405-1414. doi:10.1016/j.healun.2010.07.005

Polanowska-Grabowska, R., Wallace, K., Field, J. J., Chen, L., Marshall, M. A., Figler, R., . . . Linden, J. (2010). P-Selectin-Mediated Platelet-Neutrophil Aggregate Formation Activates Neutrophils in Mouse and Human Sickle Cell Disease. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 30(12), 2392-U123. doi:10.1161/ATVBAHA.110.211615

Yang, M., Chordia, M. D., Li, F., Huang, T., Linden, J., & Macdonald, T. L. (2010). Neutrophil- and Myeloperoxidase-Mediated Metabolism of Reduced Nimesulide: Evidence for Bioactivation. CHEMICAL RESEARCH IN TOXICOLOGY, 23(11), 1691-1700. doi:10.1021/tx1001496

Sun, W. -C., Berghaus, L. J., Moore, J. N., Hurley, D. J., Vandenplas, M. L., Thompson, R., & Linden, J. (2010). Lipopolysaccharide and TNF-α modify adenosine A2A receptor expression and function in equine monocytes. VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, 135(3-4), 289-295. doi:10.1016/j.vetimm.2009.12.001

Wallace, K. L., & Linden, J. (2010). Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. BLOOD, 116(23), 5010-5020. doi:10.1182/blood-2010-06-290643

Wang, H., Zhang, W., Tang, R., Zhu, C., Bucher, C., Blazar, B. R., . . . Huo, Y. (2010). Adenosine Receptor A2A Deficiency in Leukocytes Increases Arterial Neointima Formation in Apolipoprotein E-Deficient Mice. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 30(5), 915-U78. doi:10.1161/ATVBAHA.109.202572

Schwindinger, W. F., Mihalcik, L. J. M., Giger, K. E., Betz, K. S., Stauffer, A. M., Linden, J., . . . Robishaw, J. D. (2010). Adenosine A2A Receptor Signaling and Golf Assembly Show a Specific Requirement for the γ7 Subtype in the Striatum. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(39), 29787-29796. doi:10.1074/jbc.M110.142620

Sun, W. -C., Moore, J. N., Hurley, D. J., Vandenplas, M. L., Fortes, B., Thompson, R., & Linden, J. (2010). Differential modulation of lipopolysaccharide-induced expression of inflammatory genes in equine monocytes through activation of adenosine A2A receptors. VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, 134(3-4), 169-177. doi:10.1016/j.vetimm.2009.08.018

Sharma, A. K., Laubach, V. E., Ramos, S. I., Zhao, Y., Stukenborg, G., Linden, J., . . . Yang, Z. (2010). Adenosine A2A receptor activation on CD4+T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury. JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 139(2), 474-482. doi:10.1016/j.jtcvs.2009.08.033

Gazoni, L. M., Walters, D. M., Unger, E. B., Linden, J., Kron, I. L., & Laubach, V. E. (2010). Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury. JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, 140(2), 440-446. doi:10.1016/j.jtcvs.2010.03.002

Chhabra, P., Wang, K., Zeng, Q., Jecmenica, M., Langman, L., Linden, J., . . . Brayman, K. L. (2010). Adenosine A2A Agonist Administration Improves Islet Transplant Outcome: Evidence for the Role of Innate Immunity in Islet Graft Rejection. CELL TRANSPLANTATION, 19(5), 597-612. doi:10.3727/096368910X491806