Mario Mellado
Group Leader
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
Soler Palacios B, Nieto C, Fajardo P, González de la Aleja A, Andrés N, et al. Growth hormone reprograms macrophages towards an anti-inflammatory and reparative profile in a MAFB-dependent manner. J Immunol 2020; 205:776-788.
Lamana A, Villares R, Seoane VI, Andrés N, Lucas P, et al. Identification of a human SOCS1 polymorphism that predicts rheumatoid arthritis severity. Front Immunol 2020; 11: 1336.
Teijeira A, Garasa S, Gato M, Alfaro C, Migueliz I, et al. CXCR1 and CXCR2 chemokine receptors agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 2020; 52: 856-871.
D’Agostino G, García-Cuesta EM, Gomariz Rosa P, Rodriguez-Frade JM and Mellado M. The multilayered complexity of the chemokine receptor system. Biochem Biophys Res Commun 2020; 528:347-358.
García-Cuesta EM, Santiago CA, Vallejo-Díaz J, Juarranz Y, Rodríguez-Frade JM, and Mellado M. The role of the CXCL12/CXCR4/ACKR3 axis in autoimmune diseases. Front Endocrinol 2019; 10: 585.
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
The chemokines receptor family are members of the GPCR family. Through interaction with chemokines, they induce a wide variety of cellular responses including cell polarisation, movement, immune and inflammatory responses, as well as the prevention of HIV-1 infection. Like a Russian matryoshka doll, the chemokine receptor system is more complex than initially envisaged. The chemokines and their receptors exist as monomers, dimers and oligomers, their expression pattern is highly regulated, and the ligands can bind distinct receptors with similar affinities. The use of novel imaging-based technologies, particularly real-time imaging modalities, has shed new light on the very dynamic conformations that chemokine receptors adopt, and that affect chemokine responses. To date, all of the chemokine receptors tested form homo- and heterodimers during their synthesis and maturation, and in such conformations reach the cell membrane.
Knowledge of the dynamic interactions between ligands and receptors, as well as their interplay with other proteins co-expressed by the cell, with lipids at the cell membrane, with the cellular cytoskeleton, and with downstream signalling machinery will be crucial to determine how they modulate cell responses. Using STimulated Emission Depletion (STED) microscopy and single particle tracking and Total Internal Reflection Fluorescence Microscopy (TIRFM) we have demonstrated the receptor organisation and signalling in living cells on the spatial and temporal scales and determined the presence of basal nanoclusters of CXCR4 in resting T cells, whose extent, dynamics, and signalling strength are modulated by the orchestrated action of the actin cytoskeleton, other molecules expressed at the cell membrane, and the ligands. This new information will transform our vision of the chemokine-mediated functions, and will hopefully identify exciting opportunities for drug discovery.
In parallel, our group has also a research line to investigate inflammatory and autoimmune disease models to test the targets and hypothesis identified on the chemokine projects.
CXCL12 triggers rapid cell polarisation and lamellipodia formation. Jurkat cells expressing CXCR4-AcGFP (green) were added on coverslips coated with fibronectin plus CXCL12, fixed and stained with anti-Rac1-GTP mAb (blue) and phalloidin (red).
CXCL12 triggers directed cell migration. Spider graphs showing directed JK cell migration towards CXCL12 (right) vs control in the absence of gradient (left). The black triangle indicates the direction of the chemokine gradient
