IL-6 and leukemia-inhibitory factor are involved in the generation of tumor-associated macrophage: regulation by IFN-γ

Tumor-associated macrophages (TAMs), the most abundant immunosuppressive myeloid cells in the tumor microenvironment, exhibit an IL-10highIL-12low profile called M2, opposite to the immunostimulatory M1. We reported that ovarian cancer ascites switched monocyte differentiation into TAM-like cells that exhibit most phenotypic and functional characteristics of TAMs, suggesting that soluble mediators are involved in the differentiation of monocytes into TAM-like cells. We observed that leukemia-inhibitory factor and IL-6, present at high concentrations in ovarian cancer ascites, skew monocyte differentiation into TAM-like cells by increasing macrophage colony-stimulating factor consumption. Moreover, we observed that IFN-γ switches established TAMs into immunostimulatory M1 cells and skews monocyte differentiation from TAM-like cells to M1s. In addition to revealing a new tumor-escape mechanism associated with TAM generation via leukemia-inhibitory factor and IL-6, these findings offer novel therapeutic perspectives to subvert TAM-induced immunosuppression and to improve antitumor immunotherapy efficacy

Treg depletion followed by intracerebral CpG-ODN injection induce brain tumor rejection

Using brain lymphoma model, we demonstrate that immunotherapy combining Treg depletion (using anti-CD25 mAb PC61) followed by intracranial CpG-ODN administration induced tumor rejection in all treated mice and led to the establishment of a memory antitumor immune response in 60% of them. This protective effect was associated with a recruitment of NK cells and, to a lesser extent, of dendritic cells, B cells and T lymphocytes. NK cell depletion abolished the protective effect of the treatment, confirming a major role of NK cells in brain tumor elimination. Each treatment used alone failed to protect brain tumor bearing mice, revealing the therapeutic benefit of combining Treg depletion and local CpG-ODN injection

Implication of scavenger receptors in the interactions between diesel exhaust particles and immature or mature dendritic cells

<p>Abstract</p> <p>Background</p> <p>The exposure to pollutants such as diesel exhaust particles (DEP) is associated with an increased incidence of respiratory diseases. However, the mechanisms by which DEP have an effect on human health are not completely understood. In addition to their action on macrophages and airway epithelial cells, DEP also modulate the functions of dendritic cells (DC). These professional antigen-presenting cells are able to discriminate unmodified self from non-self thanks to pattern recognition receptors such as the Toll like Receptors (TLR) and Scavenger Receptors (SR). SR were originally identified by their ability to bind and internalize modified lipoproteins and microorganisms but also particles and TLR agonists. In this study, we assessed the implication of SR in the effects of DEP associated or not with TLR agonists on monocyte-derived DC (MDDC). For this, we studied the regulation of CD36, CXCL16, LOX-1, SR-A1 and SR-B1 expression on MDDC treated with DEP associated or not with TLR2, 3 and 4 ligands. Then, the capacity of SR ligands (dextran sulfate and maleylated-ovalbumin) to block the effects of DEP on the function of lipopolysaccharide (LPS)-activated DC has been evaluated.</p> <p>Results</p> <p>Our data demonstrate that TLR2 agonists mainly augmented CXCL16, LOX-1 and SR-B1 expression whereas DEP alone had only a weak effect. Interestingly, DEP modulated the action of TLR2 and TLR4 ligands on the expression of LOX-1 and SR-B1. Pretreatment with the SR ligand maleylated-ovalbumin but not dextran sulfate inhibited the endocytosis of DEP by MDDC. Moreover, this SR ligand blocked the effect by DEP at low dose (1 μg/ml) on MDDC phenotype (a decrease of CD86 and HLA-DR expression) and on the secretion of CXCL10, IL-12 and TNF-α. In contrast, the decrease of IL-12 and CXCL10 secretion and the generation of oxygen metabolite induced by DEP at 10 μg/ml was not affected by SR ligands</p> <p>Conclusion</p> <p>Our results show for the first time that the modulation of DC functions by DEP implicates SR. TLR agonists upregulated SR expression in contrast to DEP. Interfering with the expression and/or the function of SR might be one way to limit the impact of DEP on lung immune response.</p

Yin Yang of immunoregulation in organ transplantation and cancer

The ‘Yin Yang of Immunoregulation: Cancer and Organ Transplantation’ meeting took place in Nantes, France on 2–3 December 2010 and was dedicated to the biology of myeloid and lymphoid immune cells in the context of cancer and transplantation. This meeting was organized by the Immunotherapy Research group of the Western France Cancer Network Cancéropole Grand-Ouest and the Immunomonitorage et Biothérapies network (IMBIO) research program, which is supported by the Région Pays de la Loire

The scavenger receptors SRA-1 and SREC-I cooperate with TLR2 in the recognition of the hepatitis C virus non-structural protein 3 by dendritic cells

Backgrounds &amp; AimsThe hepatitis C virus NS3 protein is taken up by myeloid cells in a TLR2-independent manner and activates myeloid cells via TLR2. This study aimed to identify the endocytic receptor(s) involved in the uptake of NS3 by myeloid cells and its relation with TLR2. Methods Inhibitors and transfected cells were used to identify the nature of the NS3-binding receptors expressed by myeloid cells. The cooperation between scavenger receptors (SRs) and TLR2 in the NS3-mediated activation of myeloid cells was evaluated using inhibitors, cells from TLR2−/− mice, and confocal microscopy. The involvement of SRs in NS3 cross-presentation was evaluated in vitro using an NS3-specific human T-cell clone. Results We observed that SRs are the main binding structures for NS3 on myeloid cells and identified the SRs SRA-1 and SREC-I as endocytic receptors for NS3. Moreover, both SRs and TLR2 cooperate in NS3-induced myeloid cell activation. Conclusion This study highlights a central role for SRs in NS3 uptake and cross-presentation, and demonstrates a tightly orchestrated cooperation between signalling and endocytic innate receptors in NS3 recognition

Role of PTX3 in Cystic Fibrosis-associated infections

PTX3, a soluble innate immunity receptor, binds to selected microbes and facilitates their clearance by phagocytes. PTX3 selectively binds to Pseudomonas aeruginosa and Aspergillus fumigatus, two microorganisms frequently colonizing the airways of patients with cystic fibrosis (CF), and sometimes causing true respiratory infections. PTX3 -/- mice are sensitive to A. fumigatus infection, highlighting the role of this protein in the protection against this pathogen. We thus hypothesized that PTX3 could be altered in CF patients and that this could be responsible, at least in part, to their susceptibility to some opportunistic pathogens. Serum and sputum samples from 30 CF patients (20 adults and 15 children) and 7 patients with chronic obstructive pulmonary disease (COPD) as the control group were analyzed for PTX3 expression and integrity by ELISA and Western-blotting, respectively. The role of endogenous or microbial proteases on recombinant human PTX3 was also analyzed. Results showed that PTX3 level was increased in CF and COPD serum, highlighting their infectious/inflammatory status, while, in contrast, PTX3 concentration was lower or undetectable in CF sputum than in COPD. Western-blotting showed that PTX3 is degraded in sputum samples from most of CF patients, but not in clinical specimens from COPD patients. The degradation of PTX3 was shown to be mediated by serine proteases. More precisely, both the neutrophil elastase and the alkaline proteinase from A. fumigatus have the ability to degrade in vitro PTX3. This study which shows that PTX3 is degraded in respiratory secretions from CF patients, provide new insights into the pathogenesis of microbial colonization of the airways and respiratory infections in CF patients, since degradation of PTX3 could be responsible, at least in part, for the sensitivity of CF patients to some opportunistic infections

IL-26, a Cytokine With Roles in Extracellular DNA-Induced Inflammation and Microbial Defense

Interleukin 26 (IL-26) is the most recently identified member of the IL-20 cytokine subfamily, and is a novel mediator of inflammation overexpressed in activated or transformed T cells. Novel properties have recently been assigned to IL-26, owing to its non-conventional cationic, and amphipathic features. IL-26 binds to DNA released from damaged cells and, as a carrier molecule for extracellular DNA, links DNA to inflammation. This observation suggests that IL-26 may act both as a driver and an effector of inflammation, leading to the establishment of a deleterious amplification loop and, ultimately, sustained inflammation. Thus, IL-26 emerges as an important mediator in local immunity/inflammation. The dysregulated expression and extracellular DNA carrier capacity of IL-26 may have profound consequences for the chronicity of inflammation. IL-26 also exhibits direct antimicrobial properties. This review summarizes recent advances on the biology of IL-26 and discusses its roles as a novel kinocidin