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

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

The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps

The long pentraxin (PTX) 3 is produced by macrophages and myeloid dendritic cells in response to Toll-like receptor agonists and represents a nonredundant component of humoral innate immunity against selected pathogens. We report that, unexpectedly, PTX3 is stored in specific granules and undergoes release in response to microbial recognition and inflammatory signals. Released PTX3 can partially localize in neutrophil extracellular traps formed by extruded DNA. Eosinophils and basophils do not contain preformed PTX3. PTX3-deficient neutrophils have defective microbial recognition and phagocytosis, and PTX3 is nonredundant for neutrophil-mediated resistance against Aspergillus fumigatus. Thus, neutrophils serve as a reservoir, ready for rapid release, of the long PTX3, a key component of humoral innate immunity with opsonic activity

IL-26 inhibits hepatitis C virus replication in hepatocytes

Publisher Copyright: © 2021 European Association for the Study of the LiverBackground & Aims: Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system. Methods: We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity. Results: We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA. Conclusions: These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses. Lay summary: This study sheds new light on the body's arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.Peer reviewe

Mise en évidence d'une altération fonctionnelle du récepteur soluble de l'immunité innée PTX3 dans la mucoviscidose

La pentraxine longue PTX3, récepteur soluble de l'immunité innée, joue un rôle important dans la protection contre certains pathogènes, en favorisant leur élimination et l'initiation de réponses immunitaires protectrices. PTX3 a notamment un rôle protecteur lors d'infections par Aspergillus fumigatus et Pseudomonas aeruginosa. La mucoviscidose, maladie héréditaire grave à transmission autosomique récessive, est caractérisée par des infections pulmonaires récurrentes, notamment par ces deux pathogènes. Nous avons donc émis l'hypothèse que le statut de PTX3 pourrait être altéré chez ces patients. L'expression et l'intégrité de PTX3 ont été analysées dans les expectorations de 51 patients atteints de mucoviscidose et de 7 patients atteints de broncho-pneumopathie chronique obstructive (BPCO). Les résultats montrent que la concentration de PTX3 est augmentée dans les sérums de patients atteints de mucoviscidose. Au contraire, la concentration de PTX3 dans les expectorations de patients atteints de mucoviscidose est considérablement plus faible que celle des patients atteints de BPCO. Cette faible concentration de PTX3 résulte d'un clivage protéolytique par l'élastase du neutrophile et par les protéases sécrétées par Aspergillus fumigatus. De manière intéressante, le domaine N-terminal de PTX3, impliqué dans la protection contre Aspergillus fumigatus, est préférentiellement dégradé par ces protéases. Cette dégradation est spécifique de la pentraxine longue PTX3 car les pentraxines courtes, CRP et SAP, ne sont pas dégradées. Ces résultats indiquent que la protéolyse sélective de PTX3 au niveau des voies respiratoires des patients atteints de mucoviscidose peut expliquer, en partie, les infections pulmonaires récurrentes par certains pathogènes.The prototypic long pentraxin PTX3, a soluble pattern recognition receptor, plays an important role in innate defense against selected pathogens, by favoring their elimination and the initiation of protective responses. PTX3 has notably beneficial effects in mice infected with Aspergillus fumigatus and Pseudomonas aeruginosa. Cystic fibrosis (CF), a severe inherited autosomal recessive disease, is characterized by recurrent lung infections, especially by these two pathogens. We thus hypothesized that the status of PTX3 may be altered in CF patients. The levels and integrity of PTX3 were analyzed in the sputum samples from 51 CF patients and 7 patients with chronic obstructive pulmonary disease (COPD). The levels of PTX3 were increased in serums from CF and COPD patients, compared to healthy subjects, reflecting their infectious status. Surprisingly, the levels of PTX3 in sputum samples were dramatically lower in CF patients than in COPD patients. The low concentrations of PTX3 resulted from a proteolysis cleavage by elastase and Aspergillus fumigatus proteases. Interestingly, the N-terminal domain of PTX3, involved in the protection against Aspergillus fumigatus, is preferentially degraded by these proteases. These results indicate that the selective proteolysis of PTX3 in the CF lung may explain, at least in part, the recurrent lung infections by PTX3-sensitive pathogens in CF patients.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

CD23, molécule de l immunité innée ?

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Immunité naturelle : structure et fonction des toll-like receptors

International audienceThe innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate naïve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules

Predicting Bone Regeneration with a Simple Blood Test

International audienceCheng and colleagues reported previously unexplored correlations between circulating levels of immune cells and biomarkers and bone regeneration, which served as support for the construction of a model ensemble that can predict bone regeneration. If validated in humans, this tool could be valuable in the management of non-union fractures

Fungal Melanin Rewires Macrophage Metabolism

International audienc