Linden Lab

Linden Lab

"Drugs that activate or inhibit adenosine receptors have great potential for controlling the inflammatory response to disease." — Joel Linden, Ph.D. // Professor Emeritus


Joel Linden, Ph.D. and his team are focused on the study of adenosine receptors that are found on the surface of cells and recognize adenosine and related compounds. Adenosine production by cells is increased when they are stressed, activated, or lack enough oxygen.

Linden is interested in adenosine’s affect on inflammatory disease processes. He found that the adenosine receptor is a powerful negative regulator of many cells of the immune system. By activating adenosine receptors, inflammatory disease processes can be inhibited. Inflammation has been recognized to play an important role in many diseases, and this discovery suggests new potential treatments for inflammation due to ischemia or autoimmunity.

Linden found that some of the anti-inflammatory effects of adenosine are due to their powerful effects on natural killer T-cells (NKT), which he found to link tissue injury to immune system activation. NKT cells are activated by ischemia reperfusion injury, which is a type of inflammation that occurs as a result of myocardial infarction or tissue transplantation. The damage caused by the immune system in these cases is can be inhibited by adenosine.

Blocking adenosine receptors can be used to stimulate the immune system. Solid tumors evade immune surveillance in part by generating large amounts of adenosine. Drugs that block adenosine receptors can be used to enhance the effectiveness of tumor vaccines.

We think that activating adenosine receptors has great potential to help control a wide-range of inflammatory diseases including arthritis, heart failure, and sickle cell anemia,” says Linden. “On the other hand, blocking adenosine receptors in cancer can help the immune system to kill tumors; this constitutes a new type of cancer immunotherapy.

From The Lab

Mar 3, 2014 // The Washington Post

Sickle cell disease once meant a short and painful life, but now there's growing hope

Jun 16, 2013 // San Diego Union Tribune

Sickle cell drug begins phase 2 trials

Jun 12, 2013

New Sickle Cell Anemia Therapy advances to Phase II Clinical Trials

La Jolla Institute, Dana Farber and BloodCenter of Wisconsin lead nationwide trial

Chronic Inflammation

La Jolla Institute’s chronic inflammation research creates pathways to understanding and treating debilitating diseases.

Linden Lab


PLoS One

Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease

Lindner JR, Belcik T, Widlansky M, Harmann LM, Karafin MS, Wandersee NJ, Puligandla M, Neuberg D, Linden J, Field JJ
Annu Rev Immunol

Purine release, metabolism, and signaling in the inflammatory response

Linden J, Koch-Nolte F, Dahl G
JCI Insight

Induction of antiinflammatory purinergic signaling in activated human iNKT cells

Yu JC, Lin G, Field JJ, Linden J
Eur J Immunol

Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to Fc and adenosine

Franco A, Kumar J, Lin G, Behnamfar N, Hisieh LE, Shimizu C, Tremoulet AH, Burns JC, Linden J
Cancer Res

A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment

Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, Lin G, Coudert JD, Stannard KA, Zitvogel L,…
Blood Adv

Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease

Field JJ, Majerus E, Gordeuk VR, Gowhari M, Hoppe C, Heeney MM, Achebe M, George A, Chu H, Sheehan B, Puligandla M,…

Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease

Davidson BP, Belcik JT, Landry G, Linden J, Lindner JR
J Immunol

Using visualization of t-distributed stochastic neighbor embedding to identify immune cell subsets in mouse tumors

Acuff NV, Linden J

Augmentation of muscle blood flow by ultrasound cavitation is mediated by ATP and purinergic signaling

Belcik JT, Davidson BP, Zie A, Wu MD, Yadava M, Qi Y, Liang S, Chon CR, Ammi AY, Field J, Harmann L, Chilian WM, Linden…
Am J Physiol Lung Cell Mol Physiol

Adenosine influences myeloid cells to inhibit aeroallergen sensitization

Pei H, Linden J
Nat Rev Immunol

Purinergic regulation of the immune system

Cekic C, Linden J
Purinergic Signalling

Characterization of Dhal salt-sensitive rats with genetic disruption of the A2B adenosine receptor gene: implications for A2B adenosine receptor signaling during hypertension

Nayak S, Khan MA, Wan TC, Pei H, Linden J, Dwinell MR, Geurts AM, Imig JD, Auchampach JA
Journal of the American Society for Echocardiography

Abnormal regulation of microvascular tone in a murine model of sickle cell disease assessed by contrast ultrasound

Wu MD, Belcik JT, Qi Y, Zhao Y, Benner C, Pei H, Linden J, Lindner JR
Bioconjugate Chemistry

Multivalent site-specific phage modification enhances the bimding affinity of receptor ligands

Beech J, Saleh L, Frentzel J, Figler H, Correa I, Baker B, Ramspacher C, Marshall M, Dasa S, Linden J, Noren CJ, Kelly…
Basic Research in Cardiology

The infarct-sparing efffect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A2A receptors

Tian Y, Marshall M, French BA, Linden J, Yang Z
Nature Communications

The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity

Sag D, Cekic C, Wu R, Linden J, Hedrick CC
Cancer Research

Meyloid expression of adenosine Q2Q receptor suppresses T and NK cell responses in the solid tumor environment

Cekic C, Day YJ, Sag D, Linden J
Cancer Research

Adenosine A2A receptors intrinsically regulate CD8+ T cells in tumor microenvironment

Cekic C, Linden J
PLoS One

Atorvastatin at reperfusion reduces myocardial infarct size in mice by activating eNOS in bone marrow-derived cells.

Tian Y, Linden J, French BA, Yang Z
American Journal of Physiology-Gastrointential and Liver Physiology

Extracellular adenosine regulates colitis through effects on lymphoid and non-lymphoid cells

Kurtz CC, Drygiannakis I, Naganuma M, Feldman SH, Bekiaris V, Linden J, Ware CF, Ernst PB
Hematology/Oncology Clinics of North America

The role of adenosine signaling in sickle cell therapeutics

Field JJ, Nathan DG, Linden J
Molecular Pharmacology

The second extracellular loop of the adenosine A1 receptor mediates activity of allosteric enhancers

Kennedy DP, McRobb FM, Leonhardt SA, Purdy M, Figler H, Marshall MA, Chordia M, Figler R, Linden J, Abagyan R, Yeager M
Journal of Experimental Medicine

Extracellular adenosine regulates naïve T cell development and pheripheral maintenance

Cekic C, Sag D, Day YJ, Linden J
PLoS One

NF-KB is activated in CD4(+) iNKT cells by sickle cell disease and mediates rapid induction of adenosine A2A receptors

Lin G, Field JJ, Yu JC, Ken R, Neuberg D, Nathan DG, Linden J
Science Signaling

Adenosin epromotes tumor metastasis

Linden, J

Sickle cell vaso-occlusion causes activation of iNKT cells that is decreased by the adenosine A2A receptor agonist regadenoson

Field JJ, Lin G, Okam MM, Majerus E, Keefer J, Onyekwere O, Ross A, Campigotto F, Neuberg D, Linden J, Nathan DG
Journal of Thoracic and Cardiovascular Surgery

Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model

Harris DA, Zhao Y, Lapar DJ, Emaminia A, Steidle JF, Stoler M, Linden J, Kron IL, Lau CL
BMC Infectious Diseases

Adenosine A2A receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment

Li Y, Figler RA, Kolling G, Bracken TC, Rieger J, Stevenson RW, Linden J, Guerrant RL, Warren CA
Infection and Immunity

Contribution of adenosine A(2B) receptors in Colstridium difficile intoxication and infection

Warren CA, Li Y. Calabrese GM, Freire RS, Zaja-Milatovic S, van Opstal E, Figler RA, Linden J, Guerrant RL
American Journal of Respiratory and Critical Care Medicine

Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia

Barletta KE, Cagnina RE, Burdick MD, Linden J, Mehrad B
Current Diabetes Reviews

The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation

Chhabra P, Linden J, Lobo P, Okusa MD, Brayman KL
Journal of Clinical Investigation

Dendritic cells tolerized with adenosine A₂AR agonist attenuate acute kidney injury

Li L, Huang L, Ye H, Song SP, Bajwa A, Lee SJ, Moser EK, Jaworska K, Kinsey GR, Day YJ, Linden J, Lobo PI, Rosin DL,…
Cardiovascular Drugs and Therapy

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

Linden J

Translational medicine: longer life for artificial joints

Linden J
Arteriosclerosis Thrombosis and Vascular Biology

Role of adenosine in response to vascular inflammation

Linden J
PLoS One

The role of fibrocytes in sickle cell lung disease

Field JJ, Burdick MD, Debaun MR, Strieter BA, Liu L, Mehrad B, Rose CE Jr, Linden J, Strieter RM
Journal of Immunological Methods

Leukocyte compartments in the mouse lung: distinguishing between marginated, interstitial, and alveolar cells in response to injury

Barletta KE, Cagnina RE, Wallace KL, Ramos SI, Mehrad B, Linden J
Journal of Immunology

Adenosine A2B receptor blockade slows growth of bladder and breast tumors

Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden J
Transactions of the American Clinical and Climatological Association

Sickle cell disease (SCD), iNKT cells, and regadenoson infusion

Nathan DG. Field J, Lin G, Neuberg D, Majerus E, Onyekwere O, Keefer J, Okam M, Ross A, Linden J
BMC Infectious Diseases

Effects of adenosine A₂A receptor activation and alanyl-glutamine in Clostridium difficile toxin-induced ileitis in rabbits and cecitis in mice

Warren CA, Calabrese GM, Li Y, Pawlowski SW, Figler RA, Rieger J, Ernst PB, Linden J, Guerrant RL
Arteriosclerosis Thrombosis and Vascular Biology

Selectin Mediated Platelet-Neutrophil Aggregate Formation Activates Neutrophils in Mouse and Human Sickle Cell Disease

Grabowskal RP, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, Gear ARL, Linden J
Annals of Thoracic Surgery

Adenosine A2A agonist improves lung function during ex vivo lung perfusion

Emaminia A, Lapar DJ, Zhao Y, Steudke JF, Harrs DA, Laubach VE, Linden J, Kron IL, Lau CL
Clinical Immunology

Targeting iNKT cells for the treatment of sickel cell disease

Field JJ, Nathan DG, Linden J
Journal of Immunology

The A2B adenosine receptor promotes TH17 differentiation via stimulation of dendritic cell IL-6

Wilson JM, Kurtz CC, Black SG, Ross WG, Alam MS, Linden J, Ernst PB
Pharmacological Reviews

International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receoptors-an update

Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Muller CE

Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans

Figler RA, Wang G, Srinivasan S, Jung DY, Zhang Z, Pankow JS, Ravid K, Fredholm B, Hedrick CC, Rich SS, Kim JK, Lanoe…
Advances in Pharmacology

Pharmacology of purine and pyrimidine receptors. Preface

Jacobson KA, Linden J
Advances in Pharmacology

Regulation of leukocyte function by adenosine receptors

Linden J
Arterioscler Thromb Vasc Biol

P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease

Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, Gear AR, Linden J

Adenosine A2A receptors induced on iNKT and NK cells reduce pulonary inflammation and injury in mice with sickle cell disease

Wallace KL, Linden J
J Heart Lung Transplant

Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development

Zhao Y, Lapar DJ, Steidle J, Emaminia A, Kron IL, Ailawadi G, Linden J, Lau CL
Chem Res Toxicol

Neutrophil- and Myeloperoxidase-Mediated Metabolism of Reduced Nimesulide: Evidence for Bioactivation

Yang M, Chordia MD, Li F, Huang T, Linden J, Macdonald TL
J Biol Chem

Adenosine A2a receptor signaling and Golf assembly show a specific requirement for the {gamma}7 subtype in the striatum

Schwindinger WF, Murphree Mihalcik LJ, Giger KE, Betz KS, Stauffer AM, Linden J, Herve D, Robishaw JD
J Thorac Cardiovasc Surg

Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury

Gazoni LM, Walters DM, Unger EB, Linden J, Kron IL, Laubach VE
Vet Immunol Immunopathol

Lipopolysaccharide and TNF-alpha modify adenosine A(2A) receptor expression and function in equine monocytes

Sun WC, Berghaus LJ, Moore JN, Hurley DJ, Vandenplas ML, Thompson R, Linden J
Bioorg Med Chem

Synthesis and evaluation of new N6-substituted adenosine-5'-N-methylcarboxamides as A3 adenosine receptor agonists

Devine SM, Gregg A, Figler H, McIntosh K, Urmaliya V, Linden J, Pouton CW, White PJ, Bottle SE, Scammells PJ
Arterioscler Thromb Vasc Biol

Adenosine receptor A2A deficiency in leukocytes increases arterial neointima formation in apolipoprotein E-deficient mice

Wang H, Zhang W, Tang R, Zhu C, Bucher C, Blazar BR, Geng JG, Zhang C, Linden J, Wu C, Huo Y
Vet Immunol Immunopathol

Differential modulation of lipopolysaccharide-induced expression of inflammatory genes in equine monocytes through activation of adenosine A2A receptors

Sun WC, Moore JN, Hurley DJ, Vandenplas ML, Fortes B, Thompson R, Linden J
J Biol Regul Homeost Agents

Selective adenosine A(2a) receptor agonists reduce the apoptosis in an experimental model of spinal cord trauma

Genovese T, Melani A, Esposito E, Paterniti I, Mazzon E, Di Paola R, Bramanti P, Linden J, Pedata F, Cuzzocrea S
J Leukoc Biol

Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Lappas CM, Liu PC, Linden J, Kang EM, Malech HL
J Thorac Cardiovasc Surg

Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury

Sharma AK, Laubach VE, Ramos SI, Zhao Y, Stukenborg G, Linden J, Kron IL, Yang Z
Cell Transplant

Adenosine A(2A) agonist administration improves islet transplant outcome: Evidence for the role of innate immunity in islet graft rejection

Chhabra P, Wang K, Zeng Q, Jecmenica M, Langman L, Linden J, Ketchum RJ, Brayman KL

Principal Investigator

Joel Linden, Ph.D.

Professor Emeritus

Joel Linden, Ph.D. was a Professor if the La Jolla Institute for Immunology and a leading expert on adenosine receptors, which are important for regulating inflammation.

Linden received a B.S. from Brown University in Applied Mathematics and Biology and a Ph.D. from the University of Virginia in Pharmacology.

Linden has devoted the past 30 years to the study of the pharmacology, physiology and molecular biology of adenosine receptors and has co-authored over 200 papers and over 30 US patents on this subject. Dr. Linden has chaired several NIH study sections, and started a successful biopharmaceutical company, Adenosine Therapeutics.

Lab Members

Yuan Lin

Scientific Associate

Graduated with BS from Nanjing University, one of the best universities in China, Yuan Lin obtained his PhD degree in Biology in Ohio State University. Dr. Yuan Lin then completed 4-year postdoc training in UCLA medical center, working with Dr. Steven Dubinett and Dr. Maie St. John on cancer immunotherapy. Dr. Yuan Lin is currently a Scientific Associate in La Jolla Institute for Immunology.

Research Focus:
Dr. Yuan Lin has more than ten years research experience in first-class US research institutes and is an expert on cancer biology and immunotherapy area. He is interested in different approaches to regulate T cell in cancer environment. His research projects include: Adenosine receptor and IDO inhibitor anti-cancer study, genetically modified immune cell with chemokine as novel cancer immunotherapy, PI3K signaling in T cell activation, as well as function of NKT cell in cancer immunology. Dr. Yuan Lin also worked on molecular mechanism to illustrate cancer metastasis and other immune related diseases.

Selected Publications:

Lin Y*, Sharma S, St John, M. CCL21 Cancer Immunotherapy. Cancers. 2014, 6, 1098-1110; doi:10.3390 (* corresponding author)

Lin Y, Luo J, Sharma S, Dubinett S, St John, M. A Cytokine/Chemokine Delivering Dendritic Cell Polymer Is Effective in Reducing Tumor Burden in an HNSCC Murine Model. Otolaryngology-Head and Neck Surgery. 2014 May 13. pii: 0194599814533775.

Lin Y, Luo J, Sharma S, Dubinett S, St John, M. p53 modulates NF-κB mediated epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncology. 2015 Oct;51(10):921-8. doi: 10.1016

Lin Y, Jon MC, Wang G, Luo J, Sharma S, Dubinett S, St John, M. p38 MAPK Mediates Epithelial-Mesenchymal Transition by Regulating p38IP and Snail in Head and Neck Squamous Cell Carcinoma. Oral Oncology. 2016 60: 81-89. doi:

Joel Linden, Ph.D.

Professor Emeritus

Joel Linden, Ph.D. was a Professor if the La Jolla Institute for Immunology and a leading expert on adenosine receptors, which are important for regulating inflammation.

Linden received a B.S. from Brown University in Applied Mathematics and Biology and a Ph.D. from the University of Virginia in Pharmacology.

Linden has devoted the past 30 years to the study of the pharmacology, physiology and molecular biology of adenosine receptors and has co-authored over 200 papers and over 30 US patents on this subject. Dr. Linden has chaired several NIH study sections, and started a successful biopharmaceutical company, Adenosine Therapeutics.

Linden Lab

Research Projects

Sickle Cell Anemia

We are conducting studies on the effects of adenosine signaling and iNKT cells on inflammation and vaso-occlusion in mice with sickle cell disease. We are conducting a clinical trial of regadenoson, a drug that activates adenosine receptors, for the treatment of vaso-occlusive pain crises in sickle cell patients.


We are evaluating the effects of targeted deletions of adenosine receptors and adenosine receptor antagonists to activate the immune system and inhibit the growth of tumors.