G protein coupled receptors in inflammation - from kinin to chemokine

At the core of all noncommunicable diseases (NCDs) such as cancer and cardiovascular disease, is inflammation, a highly complexed process tightly orchestrating the action of multiple inflammatory molecules. Among the receptors expressed by the hematopoietic and non-hematopoietic cells, G protein-coupled receptors (GPCRs) play a key role in inflammation as they are activated by different inflammatory molecules such as amines, peptides, eicosanoids, and chemokines. The first studies summarized here unveiled a novel pathway of inflammation involving the interconnection between two GPCRs, namely the kinin B1 receptor (B1R) and the CXC chemokine receptor 2 (CXCR2). The inflammatory cytokine, IL-1β, and proatherogenic factors were identified to induce the production of the CXCL5 chemokine in endothelial cells through a B1R-dependent mechanism in acute conditions. In turn, the release of CXCL5 at the surface of endothelial cells resulted in the recruitment of CXCR2+ neutrophils into the inflamed tissue. The next study highlighted an unexpected role for the CXCL5 chemokine in chronic inflammatory disease. While CXCL5 was highly expressed by endothelial cells, its induction was protective in atherosclerotic conditions. CXCL5 was found to activate macrophages, increase the expression of ACBA1, a transporter that mediates cholesterol efflux, and consequently regulate foam cell formation. The last studies focused on a particular class of chemokine receptors, so-called atypical chemokine receptors (ACKRs) and more specifically on ACKR1, which is highly expressed by erythroblasts in the bone marrow. ACKR1 was identified as a regulator of homeostasis of haematopoietic stem and progenitor cells (HSPCs) and to control downstream hematopoiesis. Notably, erythroblasts were shown to directly interact with HSPCs in an ACKR1-dependent manner. In the absence of ACKR1, steady-state haematopoiesis was altered, bone marrow HSPCs localized remotely from erythroblasts and gave rise to phenotypically distinct neutrophils. Altogether, the work presented here provides additional evidence that the chemokine system via its action on the classical but also the atypical chemokine receptors, plays a crucial role on hematopoietic cells and in inflammation. Moreover, this work highlights the complexity of chemokine targeting in NCDs, as the same chemokine may have distinct biological effects in different inflammatory diseases. Further research is therefore required to fully apprehend the contribution of GPCRs and especially ACKRs in NCDs, to elucidate pathological mechanisms, and to ultimately develop new drug therapies targeting these receptors

Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype

Aims Acute myocardial infarction (MI) is the leading cause of mortality worldwide. Anti-inflammatory strategies to reduce neutrophil-driven acute post-MI injury have been shown to limit acute cardiac tissue damage. On the other hand, whether neutrophils are required for resolving post-MI inflammation and repair is unknown. Methods and results We show that neutrophil-depleted mice subjected to MI had worsened cardiac function, increased fibrosis, and progressively developed heart failure. Flow cytometry of blood, lymphoid organs and digested hearts revealed reduced numbers of Ly6C(high) monocytes in infarcts of neutrophil-depleted mice, whereas the number of macrophages increased, which was paralleled by reduced splenic Ly6C(high) monocyte mobilization but enhanced proliferation of cardiac macrophages. Macrophage subtype analysis revealed reduced cardiac expression of M1 markers, whereas M2 markers were increased in neutrophil-depleted mice. Surprisingly, we found reduced expression of phagocytosis receptor myeloid-epithelial-reproductive tyrosine kinase, a marker of reparative M2c macrophages which mediate clearance of apoptotic cells. In agreement with this finding, neutrophil-depleted mice had increased numbers of TUNEL-positive cells within infarcts. We identified neutrophil gelatinase-associated lipocalin (NGAL) in the neutrophil secretome as a key inducer of macrophages with high capacity to engulf apoptotic cells. The cardiac macrophage phenotype in neutrophil-depleted mice was restored by administration of neutrophil secretome or NGAL. Conclusion Neutrophils are crucially involved in cardiac repair after MI by polarizing macrophages towards a reparative phenotype. Therapeutic strategies to reduce acute neutrophil-driven inflammation after MI should be carefully balanced as they might interfere with the healing response and cardiac remodelling

Regulation of β1 Integrin-Klf2-mediated angiogenesis by CCM proteins

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Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted

First Resolved Scattered-Light Images of Four Debris Disks in Scorpius-Centaurus with the Gemini Planet Imager

We present the first spatially resolved scattered-light images of four debris disks around members of the Scorpius-Centaurus (Sco-Cen) OB association with high-contrast imaging and polarimetry using the Gemini Planet Imager (GPI). All four disks are resolved for the first time in polarized light, and one disk is also detected in total intensity. The three disks imaged around HD 111161, HD 143675, and HD 145560 are symmetric in both morphology and brightness distribution. The three systems span a range of inclinations and radial extents. The disk imaged around HD 98363 shows indications of asymmetries in morphology and brightness distribution, with some structural similarities to the HD 106906 planet-disk system. Uniquely, HD 98363 has a wide comoving stellar companion, Wray 15-788, with a recently resolved disk with very different morphological properties. HD 98363 A/B is the first binary debris disk system with two spatially resolved disks. All four targets have been observed with ALMA, and their continuum fluxes range from one nondetection to one of the brightest disks in the region. With the new results, a total of 15 A/F stars in Sco-Cen have resolved scattered-light debris disks, and approximately half of these systems exhibit some form of asymmetry. Combining the GPI disk structure results with information from the literature on millimeter fluxes and imaged planets reveals a diversity of disk properties in this young population. Overall, the four newly resolved disks contribute to the census of disk structures measured around A/F stars at this important stage in the development of planetary systems

Imaging the 44 au Kuiper Belt Analog Debris Ring around HD 141569A With GPI Polarimetry

We present the first polarimetric detection of the inner disk component around the pre-main-sequence B9.5 star HD 141569A. Gemini Planet Imager H-band (1.65 μm) polarimetric differential imaging reveals the highest signal-to-noise ratio detection of this ring yet attained and traces structure inward to 0.″25 (28 au at a distance of 111 pc). The radial polarized intensity image shows the east side of the disk, peaking in intensity at 0.″40 (44 au) and extending out to 0.″9 (100 au). There is a spiral arm-like enhancement to the south, reminiscent of the known spiral structures on the outer rings of the disk. The location of the spiral arm is coincident with 12CO J = 3-2 emission detected by ALMA and hints at a dynamically active inner circumstellar region. Our observations also show a portion of the middle dusty ring at ∼220 au known from previous observations of this system. We fit the polarized H-band emission with a continuum radiative transfer Mie model. Our best-fit model favors an optically thin disk with a minimum dust grain size close to the blowout size for this system, evidence of ongoing dust production in the inner reaches of the disk. The thermal emission from this model accounts for virtually all of the far-infrared and millimeter flux from the entire HD 141569A disk, in agreement with the lack of ALMA continuum and CO emission beyond ∼100 au. A remaining 8-30 μm thermal excess a factor of ∼2 above our model argues for an as-yet-unresolved warm innermost 5-15 au component of the disk

Regulation of monocyte cell fate by blood vessels mediated by Notch signalling

A population of monocytes, known as Ly6Clo monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6Chi monocytes into Ly6Clo monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation

Regulation of monocyte cell fate by blood vessels mediated by Notch signalling

A population of monocytes, known as Ly6C(lo) monocytes, patrol blood vessels by crawling along the vascular endothelium. Here we show that endothelial cells control their origin through Notch signalling. Using combinations of conditional genetic deletion strategies and cell-fate tracking experiments we show that Notch2 regulates conversion of Ly6C(hi) monocytes into Ly6C(lo) monocytes in vivo and in vitro, thereby regulating monocyte cell fate under steady-state conditions. This process is controlled by Notch ligand delta-like 1 (Dll1) expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow and spleen in vivo, while culture on recombinant DLL1 induces monocyte conversion in vitro. Thus, blood vessels regulate monocyte conversion, a form of committed myeloid cell fate regulation