Joel M Linden
- Email: jl4v@virginia.edu
- Phone: 434-243-6358
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
Personal Statement
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