Chemokine receptors: new targets for therapeutic intervention

MMellado

 

Mario Mellado

Group Leader

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Research summary

Through their interactions with G protein-coupled receptors, the chemokines have a key role in a broad array of biological responses that include cell polarisation and movement, immune and inflammatory responses, haematopoiesis, tumour rejection and prevention of HIV-1 infection.

 

Publications

Martínez-Muñoz L, Rodríguez-Frade JM, Barroso R, Sorzano CO, Torreño-Pina JA, Santiago CA, Manzo C, Lucas P, García-Cuesta EM, Gutierrez E, Barrio L, Vargas J, Cascio G, Carrasco YR, Sánchez-Madrid F, García-Parajo MF, Mellado M. Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function. Mol Cell 2018; 70:106-119.e1070:106-119.e10

Rodriguez-Frade JM, Guedán AI, Lucas P, Martínez-Muñoz L, Villares R, Criado G, Balomenos D, Reyburn HT, Mellado M. Use of Lentiviral Particles as a Cell Membrane-Based mFasL Delivery System for in Vivo treatment of Inflammatory Arthritis. Frontiers Immunol, 2017; 8:460-469

Collins PJ, McCully ML, Martínez-Muñoz L, Santiago C, Wheeldon J, Caucheteux S, Thelen S, Cecchinato V, Laufer JM, Purvanov V, Monneau YR, Lortat-Jacob H, Legler DF, Uguccioni M, Thelen M, Piguet V, Mellado M, Moser B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. The FASEB Journal, 2017; 31(7):3084-3097

Martínez-Muñoz L, Rodríguez-Frade JM, Mellado M. Use of Resonance Energy Transfer techniques for in vivo detection of chemokine receptor oligomerization. Chemotaxis (Methods in Molecular Biology vol 1407). Ed. Tian Ji and Dale Hereld. Humana Press Totowa NJ (USA) Ch 1407:341-359 (2016)

Mellado M, Martínez Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM. T cell migration in rheumatoid arthritis. Front Immunol, 2015; 6:384-396

Cascio G, Martín-Cófreces NB, Rodríguez-Frade JM, López-Cotarelo P, Criado G, Pablos JL, Rodríguez-Fernández JL, Sánchez-Madrid F, Mellado M. CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses. The Journal of Immunology 2015; 194: 5509-5519.

 

Mellado Figure 2

A broad array of biological responses including cell polarization, movement, immune and inflammatory responses, and prevention of HIV-1 infection are triggered by the chemokines, a family of secreted, structurally related chemoattractant proteins that bind to class A- specific G protein-linked seven-transmembrane receptors.  The chemokines and their receptors should not be considered isolated entities, as they act in complex networks.  Chemokines bind as oligomers, or oligomerize after binding to glycosaminoglycans on endothelial cells; they are then presented to their receptors on target cells, which facilitates the generation of chemoattractant gradients.  At the cell surface, these receptors form homo- and heterodimers as well as higher order dynamic structures that are regulated by receptor expression and ligand levels.

To characterize these processes, our group applies advanced light microscopy techniques.  We use total internal reflection fluorescent microscopy (TIRF) and single particle tracking to determine the spatio-temporal organization of these receptors on the cell membrane, and super-resolution microscopy (STED) to achieve spatial resolutions of ~30 nm on intact cells.   These technologies allow us to study how chemokine receptors diffuse across the cell membrane and the types of trajectories they use, how the ligand alters these processes, and how factors such as the actin cytoskeleton or other co-expressed proteins control receptor motion and regulate the link between the signaling machinery and cell function.

In addition, we are analyzing the oligomerization motif, for which we are developing in silico methods to identify small compounds that, by binding this motif, allow us to intervene in chemokine function.  To test these drug candidates in in vivo systems, we use mouse models of autoimmunity, in which we also analyze the in vivo importance of our in vitro findings and test how factors such as hormones and neurotransmitters might alter our observations.

The classical approach to altering chemokine function –blocking a chemokine or receptor binding site– turned out to be overly simplistic.  Our research reanalyzes chemokine biology to define new therapeutic targets for inflammatory and autoimmune diseases.

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Mellado Figure 1

TIRF-M images of unstimulated (left) or CXCL12-activated (right)
JK cells transiently transfeted with CXCR4-AcGFP

 

Mellado Figure 3

JK (left) and JKCD4+(right) cells transiently transfected with CXCR4-Ac GFP

were allow to adhere on lipid bilayers containing ICAM-1 alone (upper) or plus CXCL12 20nM (bottom)

 

 

 

 grupoMelladoRed 

Name
Position
Contact
Mario Mellado Principal investigator
José Miguel Rodríguez Frade Senior scientist
Ricardo Villares Senior scientist
Eva Mª García Cuesta Postdoctoral scientist
Blanca Soler Palacios Postdoctoral scientist
Pablo Martínez Predoctoral scientist
Mª Pilar Lucas Technician
Nuria Andrés Technician

ComFuturo Vertical

La Fundación General CSIC, financia a través del Programa ComFuturo el contrato de la investigadora Laura Martínez Muñoz para la realización del proyecto "Estrategias terapéuticas basadas en quimioquinas para el tratamiento de enfermedades inflamatorias crónicas".

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