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1.  CX3CL1 (fractalkine) and its receptor CX3CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin 
The Journal of Experimental Medicine  2014;211(6):1185-1196.
Fractalkine interactions with its receptor, CX3CR1, regulate CD4+ T cell retention in atopic dermatitis and offer a potential therapeutic target in allergic disease.
Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1–CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4+ T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4+ T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.
doi:10.1084/jem.20121350
PMCID: PMC4042636  PMID: 24821910
2.  Beneficial Metabolic Effects of Rapamycin Are Associated with Enhanced Regulatory Cells in Diet-Induced Obese Mice 
PLoS ONE  2014;9(4):e92684.
The “mechanistic target of rapamycin” (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases.
doi:10.1371/journal.pone.0092684
PMCID: PMC3977858  PMID: 24710396
3.  p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages 
Blood  2011;118(9):2556-2566.
The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize towards classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined.
Here, we show that p16INK4a-deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− bone marrow-derived macrophages (BMDM) exhibit a phenotype resembling interleukin (IL)-4-induced macrophage polarization. In line with this observation, p16−/− BMDM displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− bone marrow displayed higher hepatic AAMφ marker expression levels upon Schistosoma mansoni infection, an in vivo model of AAMφ phenotype-skewing. Surprisingly, p16−/− BMDM did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and LPS-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.
doi:10.1182/blood-2010-10-313106
PMCID: PMC3677739  PMID: 21636855
Animals; Bone Marrow Transplantation; Cyclin-Dependent Kinase Inhibitor p16; deficiency; physiology; Cytokines; biosynthesis; Genes, p16; I-kappa B Kinase; physiology; Inflammation; genetics; Interferon-gamma; pharmacology; Interleukin-4; pharmacology; Janus Kinase 2; physiology; Lipopolysaccharides; pharmacology; Liver; metabolism; pathology; Macrophage Activation; drug effects; Macrophages; drug effects; physiology; Mice; Mice, Inbred C57BL; Phosphorylation; Protein Processing, Post-Translational; Radiation Chimera; STAT1 Transcription Factor; physiology; STAT6 Transcription Factor; physiology; Schistosomiasis; immunology; Signal Transduction
4.  GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation 
Cell & Bioscience  2012;2:34.
Background
After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl4) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl4 alone or CCl4 co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ.
Results
We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl4/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway.
Conclusions
This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.
doi:10.1186/2045-3701-2-34
PMCID: PMC3519722  PMID: 23046570
Peroxisome proliferator-activated receptor β/δ; Inflammation; Fibrosis; Signaling pathways; Proliferation
5.  EMBO workshop on immunology and metabolism 
EMBO Reports  2011;12(5):386-388.
Recent findings have identified roles for the immune system in what had been considered prototypic metabolic diseases, while metabolic control has emerged as an important determinant of immune function. Giovanna Chimini, Lee Leserman, Diane Mathis and Philippe Naquet organized the EMBO Workshop on Immunology and Metabolism, which took place in January 2011 at the Centre d’Immunologie de Marseille-Luminy in Marseille, France. The meeting brought together around 100 scientists to discuss interactions between metabolism and inflammation, and was sponsored by Sanofi-Aventis and the CIML.
doi:10.1038/embor.2011.68
PMCID: PMC3090031  PMID: 21494247
Allergy and Immunology; trends; Metabolic Diseases; immunology; Metabolism; immunology
6.  A Functional γδTCR/CD3 Complex Distinct from γδT Cells Is Expressed by Human Eosinophils 
PLoS ONE  2009;4(6):e5926.
Background
Eosinophils are effector cells during parasitic infections and allergic responses. However, their contribution to innate immunity has been only recently unravelled.
Methodology/Principal Findings
Here we show that human eosinophils express CD3 and γδ T Cell Receptor (TCR) but not αβ TCR. Surface expression of γδTCR/CD3 is heterogeneous between eosinophil donors and inducible by mycobacterial ligands. Surface immunoprecipitation revealed expression of the full γδTCR/CD3 complex. Real-time PCR amplification for CD3, γ and δ TCR constant regions transcripts showed a significantly lower expression in eosinophils than in γδT cells. Limited TCR rearrangements occur in eosinophils as shown by spectratyping analysis of CDR3 length profiles and in situ hybridization. Release by eosinophils of Reactive Oxygen Species, granule proteins, Eosinophil Peroxidase and Eosinophil-Derived Neurotoxin and cytokines (IFN-γ and TNF-α) was observed following activation by γδTCR-specific agonists or by mycobacteria. These effects were inhibited by anti-γδTCR blocking antibodies and antagonists. Moreover, γδTCR/CD3 was involved in eosinophil cytotoxicity against tumor cells.
Conclusions/Significance
Our results provide evidence that human eosinophils express a functional γδTCR/CD3 with similar, but not identical, characteristics to γδTCR from γδT cells. We propose that this receptor contributes to eosinophil innate responses against mycobacteria and tumors and may represent an additional link between lymphoid and myeloid lineages.
doi:10.1371/journal.pone.0005926
PMCID: PMC2693924  PMID: 19536290
7.  Peroxisome Proliferator–activated Receptors α and γ Down-regulate Allergic Inflammation and Eosinophil Activation 
Allergic asthma is characterized by airway hyperresponsiveness, eosinophilia, and mucus accumulation and is associated with increased IgE concentrations. We demonstrate here that peroxisome proliferator–activated receptors (PPARs), PPAR-α and PPAR-γ, which have been shown recently to be involved in the regulation of various cell types within the immune system, decrease antigen-induced airway hyperresponsiveness, lung inflammation, eosinophilia, cytokine production, and GATA-3 expression as well as serum levels of antigen-specific IgE in a murine model of human asthma. In addition, we demonstrate that PPAR-α and -γ are expressed in eosinophils and their activation inhibits in vitro chemotaxis and antibody-dependent cellular cytotoxicity. Thus, PPAR-α and -γ (co)agonists might be of therapeutic interest for the regulation of allergic or inflammatory reactions by targeting both regulatory and effector cells involved in the immune response.
doi:10.1084/jem.20021384
PMCID: PMC2194090  PMID: 12900517
nuclear receptors; asthma; eosinophils; IgE; ADCC
8.  Role of the High Affinity Immunoglobulin E Receptor in Bacterial Translocation and Intestinal Inflammation 
A role for immunoglobulin E and its high affinity receptor (FcεRI) in the control of bacterial pathogenicity and intestinal inflammation has been suggested, but relevant animal models are lacking. Here we compare transgenic mice expressing a humanized FcεRI (hFcεRI), with a cell distribution similar to that in humans, to FcεRI-deficient animals. In hFcεRI transgenic mice, levels of colonic interleukin 4 were higher, the composition of fecal flora was greatly modified, and bacterial translocation towards mesenteric lymph nodes was increased. In hFcεRI transgenic mice, 2,4,6-tri-nitrobenzenesulfonic acid (TNBS)-induced colitis was also more pronounced, whereas FcεRI-deficient animals were protected from colitis, demonstrating that FcεRI can affect the onset of intestinal inflammation.
PMCID: PMC2195885  PMID: 11136818
immunoglobulin E receptor; bacterial translocation; intestinal permeability; inflammatory bowel disease; colitis
9.  Natural Killer Cells and Mast Cells from gp49B Null Mutant Mice Are Functional 
Molecular and Cellular Biology  2000;20(19):7178-7182.
Immune responses are controlled by a combination of positive and negative cellular signals. Effector cells in the immune system express inhibitory receptors that serve to limit effector cell expansion and to protect the host from autoreactivity. gp49B is a receptor of unknown function that is expressed on activated mast cells and natural killer (NK) cells and whose cytoplasmic tail endows it with inhibitory potential. To gain insight into the function of gp49B in mice, we disrupted the gp49B gene by homologous recombination. gp49B0 mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. gp49B0 mice showed no defect in NK or mast cell development. Furthermore, NK and mast cells from the gp49B0 mice showed activation properties in vitro similar to those of cells isolated from wild-type mice. Therefore, gp49B is not critical for the development, expansion, and maturation of mast cells and NK cells in vivo. The healthy status of gp49B0 mice makes them suitable for testing the role of gp49B in immune responses to infectious agents.
PMCID: PMC86271  PMID: 10982834
10.  Expression of Cd28 and Cd86 by Human Eosinophils and Role in the Secretion of Type 1 Cytokines (Interleukin 2 and Interferon γ) 
Eosinophils are the source of various immunoregulatory cytokines, but the membrane molecules involved in their secretion have not been clearly identified. Here we show that peripheral blood eosinophils from hypereosinophilic patients could express membrane CD86 but not CD80. The T cell costimulatory molecule CD28 is also detected on the eosinophil surface. CD28 ligation but not CD86 ligation resulted in interleukin (IL)-2 and interferon (IFN)-γ secretion by eosinophils, whereas IL-4, IL-5, and IL-10 were not detected. In contrast to T cells requiring two signals for effective stimulation, CD28 ligation alone was sufficient for optimal eosinophil activation. Eosinophil-derived IL-2 and IFN-γ were biologically active, as supernatants from anti-CD28–treated cells were able to induce CTLL-2 proliferation and major histocompatibility complex class II expression on the colon carcinoma cell line Colo 205, respectively. Addition of secretory immunoglobulin (Ig)A–anti-IgA complexes, which could induce the release of IL-10, very significantly inhibited both CD28-mediated IL-2 and IFN-γ release. These results suggest that the release of type 1 (IFN-γ and IL-2) versus type 2 cytokines by eosinophils is not only differential but also dependent on cross-regulatory signals. They confirm that through activation of costimulatory molecules, eosinophils could function as an immunoregulatory cell involved in the release of both type 1 and type 2 cytokines.
PMCID: PMC2195599  PMID: 10449520
eosinophils; CD28; CD86; type 1 cytokines; secretory IgA

Results 1-10 (10)