José Rodríguez-Fernández

The Multiple Personalities of the Chemokine Receptor CCR7 in Dendritic Cells

CCR7 was described initially as a potent leukocyte chemotactic receptor that was later shown to be responsible of directing the migration of dendritic cells (DCs) to the lymph nodes where these cells play an important role in the initiation of the immune response. Recently, a variety of reports have indicated that, apart from chemotaxis, CCR7 controls the cytoarchitecture, the rate of endocytosis, the survival, the migratory speed, and the maturation of the DCs. Some of these functions of CCR7 and additional ones also have been described in other cell types. Herein we discuss how this receptor may contribute to modulate the immune response by regulating different functions in DCs. Finally, we also suggest a possible mechanism whereby CCR7 may control its multiple tasks in these cells.

CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2/CCR2-Dependent Gene Expression Profile

The CCL2 chemokine mediates monocyte egress from bone marrow and recruitment into inflamed tissues through interaction with the CCR2 chemokine receptor, and its expression is upregulated by proinflammatory cytokines. Analysis of the gene expression profile in GM-CSF– and M-CSF–polarized macrophages revealed that a high CCL2 expression characterizes macrophages generated under the influence of M-CSF, whereas CCR2 is expressed only by GM-CSF–polarized macrophages. Analysis of the factors responsible for this differential expression identified activin A as a critical factor controlling the expression of the CCL2/CCR2 pair in macrophages, as activin A increased CCR2 expression but inhibited the acquisition of CCL2 expression by M-CSF–polarized macrophages. CCL2 and CCR2 were found to determine the extent of macrophage polarization because CCL2 enhances the LPS-induced production of IL-10, whereas CCL2 blockade leads to enhanced expression of M1 polarization-associated genes and cytokines, and diminished expression of M2-associated markers in human macrophages. Along the same line, Ccr2-deficient bone marrow–derived murine macrophages displayed an M1-skewed polarization profile at the transcriptomic level and exhibited a significantly higher expression of proinflammatory cytokines (TNF-α, IL-6) in response to LPS. Therefore, the CCL2-CCR2 axis regulates macrophage polarization by influencing the expression of functionally relevant and polarization-associated genes and downmodulating proinflammatory cytokine production.

Autopsy on a dead spreading center: The Phoenix Ridge, Drake Passage, Antarctica

New bathymetric and magnetic anomaly data from the Phoenix Ridge, Antarctica, show that extinction of all three remaining segments occurred at the time of magnetic chron C2A (3.3 ± 0.2 Ma), synchronous with a ridge-trench collision south of the Hero Fracture Zone. This implies that the ultimate cause of extinction was a change in plate boundary forces occasioned by this collision. Spreading rates slowed abruptly at the time of chron C4 (7.8 ± 0.3 Ma), probably as a result of extinction of the West Scotia Ridge, which would have led to an increase in slip rate and transpressional stress across the Shackleton Fracture Zone. Spectacular, high-relief ridges flanking the extinct spreading center, mapped for the first time using multibeam swath bathymetry, are interpreted as a consequence of a reduction in spreading rate, involving a temporary magma oversupply immediately prior to extinction.

Contourite deposits in the central Scotia Sea: the importance of the Antarctic Circumpolar Current and the Weddell Gyre flows

Abstract New swath bathymetry with multichannel and high resolution seismic profiles shows a variety of contourite drift, sediment wave morphologies, and seismic facies in the central Scotia Sea. The deposits are to be found at the confluence between the two most important bottom current flows in the southern ocean: the eastward flowing Antarctic Circumpolar Current (ACC) and the northward outflow of the Weddell Sea Deep Water (WSDW). The contourite drifts are wedge-like deposits up to 1 km thick, that exhibit aggradational reflectors along axis thinning towards the margins. The contourite drifts occur in areas of weaker flows along the margins of contourite channels and in areas protected by obstacles. The elongate-mounded drifts are best developed along the left-hand margins of channelized bottom current flows, due to the Coriolis force. A contourite fan has a main channel and two distributary channels that expand over a gentle seafloor. The proximal fan exhibits sediment waves with the distal fan incised by furrows. Sediment wave fields are well developed in areas of intensified bottom flows without channels, particularly at the confluence of the ACC and the WSDW. Small sediment waves occur where unidirectional bottom current flows predominate. Sediment waves may develop under the influence of internal waves produced by the interaction of the flows and sea-bottom relief. The stratigraphic sequence above the oceanic crust of Early to Middle Miocene age contains six seismic units separated by major reflectors. All the units were shaped under the influence of strong bottom current flows, although they exhibit distinct seismic facies changes that record the variations of the bottom current pathways over time. The age of the units was calculated based on the age of the oceanic crust and sedimentation rates of deep-sea deposits in the region. The oldest, Units VI–IV, are of Early to Middle Miocene age and developed under the influence of the ACC. They are characterized by a southward progradational pattern of the seismic units and sedimentation rates of 5–8 cm/ky. Unit III, with an estimated Middle Miocene age, evidences the first incursion of WSDW into the central Scotia Sea, when plate movement caused openings in the South Scotia Ridge and allowed the connection with the northern Weddell Sea through Jane Basin and gaps in the ridge. Unit II, estimated to be of Late Miocene to Early Pliocene age, extends over the area and is characterized by internal unconformities. A major unconformity at the base of Unit II records an important reorganization of bottom current flows that may predate the onset of grounded ice sheets on the Antarctic Peninsula shelf. Unit I, of Late Pliocene to Quaternary age, shows intensified bottom currents. The unconformity at the base of Unit I probably predates the onset of major Northern Hemisphere glaciations and the greater expansion of Antarctic ice sheets during the Late Pliocene. The extensive distribution of contourite deposits above the oceanic crust testifies to the long-term production of Antarctic Bottom Water. Cold, deep water was swept northward from the Weddell Gyre, interacting with the ACC, and possibly exerting profound influences on the global circulation system and the onset of major glaciations.

Small ocean basin development along the Scotia–Antarctica plate boundary and in the northern Weddell Sea

Abstract The oceanic crust of the northern Weddell Sea and Scotia Sea contains the following principal morphostructural elements: (1) the South Scotia Ridge and the South Orkney Microcontinent, both with continental crust; (2) the oceanic Powell and Jane basins; and (3) Jane Bank, which belongs to an island arc. The analysis of MCS profiles and of gravimetric and magnetic data from Russian, Italian and Spanish cruises, supplemented with satellite gravimetric data, has enabled us to determine the relationship between these elements and to propose a model for the main stages of Cenozoic evolution in the area. During the early Cenozoic, the Weddell Sea oceanic crust was subducted under the southern margin of the South Orkney Microcontinent. The subduction probably ended westwards at the South Powell Ridge, a submarine extension of the Antarctic Peninsula. A major transcurrent fault zone is identified in the northwestern Weddell Sea, bounding oceanic crust of Mesozoic and Cenozoic ages. This fault zone was probably active at least to the Miocene. The drifting of the South Orkney Microcontinent from the Antarctic Peninsula during the late Eocene to early Miocene originated the Powell Basin. Jane Basin developed as a backarc, related to the subduction of the Weddell Sea oceanic crust below Jane Bank. The seismic stratigraphy of the depositional sequences in these two basins indicates that spreading in Jane Basin started simultaneously with the end of the opening in Powell Basin. The active spreading ridge of the Weddell Sea collided with the trench and was subducted below Jane Bank at 15–20 Ma. Drifting in Jane Basin and subduction below Jane Bank ended shortly thereafter, in the middle Miocene, and the boundary between the Antarctic/Scotia plates migrated north of the South Orkney Microcontinent, along the South Scotia Ridge. Present tectonic activity in the region is minor.

Immunological synapse formation inhibits, via NF-κB and FOXO1, the apoptosis of dendritic cells

The immunological synapse (IS) is a cell–cell junction formed between CD4+ T cells and dendritic cells (DCs). Here we show in vitro and in vivo that IS formation inhibits apoptosis of DCs. Consistent with these results, IS formation induced antiapoptotic signaling events, including activation of the kinase Akt1 and localization of the prosurvival transcription factor NF-κB and the proapoptotic transcription factor FOXO1 to the nucleus and cytoplasm, respectively. Inhibition of phosphatidylinositol 3-OH kinase and Akt1 partially prevented the antiapoptotic effects of IS formation. Direct stimulation of the IS component CD40 on DCs leads to the activation of Akt1, suggesting the involvement of this receptor in the antiapoptotic effects observed upon IS formation.

Polysialylated neuropilin-2 enhances human dendritic cell migration through the basic C-terminal region of CCL21

Dendritic cell (DC) migration to secondary lymphoid organs is a critical step to properly exert its role in immunity and predominantly depends on the interaction of the chemokine receptor CCR7 with its ligands CCL21 and CCL19. Polysialic acid (PSA) has been recently reported to control CCL21-directed migration of mature DCs. Here, we first demonstrate that PSA present on human mature monocyte-derived dendritic cells did not enhance chemotactic responses to CCL19. We have also explored the molecular mechanisms underlying the selective enhancing effect of PSA on CCL21-driven chemotaxis of DCs. In this regard, we found out that prevention of DC polysialylation decreased CCL21 activation of JNK and Akt signaling pathways, both associated with CCR7-mediated chemotaxis. We also report that the enhanced PSA-mediated effect on DC migration towards CCL21 relied on the highly basic C-terminal region of this chemokine and depended on the PSA acceptor molecule neuropilin-2 (NRP2) and on the polysialyltransferase ST8SiaIV. Altogether, our data indicate that the CCR7/CCL21/NRP2/ST8SiaIV functional axis constitutes an important guidance clue for DC targeting to lymphoid organs.

Polysialic acid is required for neuropilin-2a/b-mediated control of CCL21-driven chemotaxis of mature dendritic cells and for their migration in vivo.

Migration of mature dendritic cells (mDCs) to secondary lymphoid organs is required for the development of immunity. Recently, we reported that polysialic acid (PSA) and the transmembrane glycoprotein neuropilin-2 (NRP2) control mDC chemotaxis to CCL21 and that this process is dependent on the C-terminal basic region of the chemokine. Herein, we provide further insight into the molecular components controlling PSA regulated chemotaxis in mDCs. In the present study, we demonstrate that human mDCs express the NRP2 isoforms NRP2a and NRP2b, that both of them are susceptible to polysialylation and that polysialylation is required to specifically enhance chemotaxis toward CCL21 in mDCs. The results presented suggest that PSA attached to NRP2 isoforms acts as a binding module for the CCL21 chemokine, thereby facilitating its presentation to the chemokine receptor CCR7. To investigate the relevance of polysialylation on mDC migration, a xenograft mouse model was used and the migration of human DCs to mouse lymph nodes analyzed. Here, we demonstrate that the depletion of PSA from mDCs results in a drastic reduction in the migration of the cells to draining popliteal lymph nodes. With this finding, we provide first evidence that PSA is a crucial factor for in vivo migration of mDCs to lymph nodes.

CD69 modulates sphingosine-1-phosphate-induced migration of skin dendritic cells

In this study, we have investigated the role of CD69, an early inducible leukocyte activation receptor, in murine dendritic cell (DC) differentiation, maturation, and migration. Skin DCs and DC subsets present in mouse lymphoid organs express CD69 in response to maturation stimuli. Using a contact sensitization model, we show that skin DCs migrated more efficiently to draining lymph nodes (LNs) in the absence of CD69. This was confirmed by subcutaneous transfer of CD69-/- DCs, which presented an increased migration to peripheral LNs. Two-photon microscopy analysis showed that once DCs reached the LNs, CD69 deficiency did not alter DC interstitial motility in the LNs. Chemotaxis to sphingosine-1-phosphate (S1P) was enhanced in CD69-/- DCs compared with wild-type DCs. Accordingly, we detected a higher expression of S1P receptor type-1 (S1P(1)) by CD69-/- DCs, whereas S1P(3) expression levels were similar in wild-type and CD69-/- DCs. Moreover, in vivo treatment with S1P analogs SEW2871 and FTY720 during skin sensitization reduced skin DC migration to peripheral LNs. These results suggest that CD69 regulates S1P-induced skin DC migration by modulating S1P(1) function. Together, our findings increase our knowledge on DC trafficking patterns in the skin, enabling the development of new directed therapies using DCs for antigen (Ag) delivery.

Extensional deformation and development of deep basins associated with the sinistral transcurrent fault zone of the Scotia–Antarctic plate boundary

Abstract The Scotia–Antarctic plate boundary extends along the southern branch of the Scotia Arc, between triple junctions with the former Phoenix plate to the west (57°W) and with the Sandwich plate to the east (30°W). The main mechanism responsible for the present arc configuration is the development of the Scotia and Sandwich plates from 30–35 Ma, related to breakup of the continental connection between South America and the Antarctic Peninsula. The Scotia–Antarctic plate boundary is a very complex tectonic zone, because both oceanic and continental elements are involved. Present-day sinistral transcurrent motion probably began 8 Ma ago. The main active structures that we observed in the area include releasing and restraining bends, with related deep extensional and compressional basins, and probable pull-apart basins. The western sector of the plate boundary crosses fragmented continental crust: the Western South Scotia Ridge, with widespread development of pull-apart basins and releasing bends deeper than 5000 m, filled by asymmetrical sedimentary wedges. The northern border of the South Orkney microcontinent, in the central sector, has oceanic and continental crust in contact along a large thrust zone. Finally, the eastern sector of the South Scotia Ridge is located within Discovery Bank, a piece of continental crust from a former arc. On its southern border, strike-slip and normal faults produce a 5500-m-deep trough that may be interpreted as a pull-apart basin. In the eastern and western South Scotia Ridge, despite extreme continental-crustal thinning, the basins show no development of oceanic crust. This geometry is conditioned by the distinctive rheological behaviour of the crust involved, with the bulk concentration of deformation within the rheologically weaker continental blocks.