Immunopathological Basis of Virus-induced Myocarditis

Heart diseases are an important cause of morbidity and mortality in industrialized countries. Dilated cardiomyopathy (DCM), one of the most common heart diseases, may be the consequence of infectionassociated myocardits. Coxsackievirus B3 (CVB3) can be frequently detected in the inflamed heart muscle. CVB3-induced acute myocarditis is most likely the consequence of direct virus-induced myocyte damage, whereas chronic CVB3 infection-associated heart disease is dominated by its immunopathological sequelae. Bona fide autoimmunity, for example, directed against cardiac myosin, may favor chronic destructive immune damage in the heart muscle and thereby promote the development of DCM. The immunopathogenesis of myocarditis and subsequent DCM induced either by pathogens or autoantigens can be investigated in well-established animal models. In this article, we review recent studies on the role of viruses, with particular emphasis on CVB3, and different immunological effector mechanisms in initiation and progression of myocarditis

L’ingénieur Krebs (1850-1935) ou comment traduire le fluide électrique

Les ingénieurs du xixe siècle ont largement manié le modèle épistémologique du fluide pour répondre aux attentes des milieux socio-économiques de leur temps. Dans le domaine de la locomotion et de la motricité, la vapeur est l’énergie de la puissance, pesante et dangereuse, et l’électricité est la nouvelle énergie universelle promise à tous les succès. L’ingénieur militaire Arthur Krebs, à la recherche de la maîtrise de la matière et de l’énergie, conçoit des objets électriques novateurs, de mobilité aérostatique et sous-marine comme des ensembles continus de fluides collectés et transportés. La jeune république française en reconstruction a des rêves de modernité et d’autonomie. L’ingénieur réorganisateur du service d’incendie de la Ville de Paris ne doit plus seulement maîtriser les fluides matériels, il doit également maîtriser le fluide-temps, aussi invisible que le fluide électrique. La vitesse mécanique et électrique est sa réponse aux exigences de fluidité. La pensée de la mobilité, de la vitesse et de l’autonomie le conduisent finalement à se faire le promoteur, chez Panhard -Levassor, de la cause automobile et du moteur à pétrole en apportant des solutions techniques dans la voie de l’hybridation du pétrole et de l’électricité, au point qu’on a pu dire alors que cette dernière avait « sauvé » le moteur à essence face aux moteurs à vapeur et électrique.The engineers of the nineteenth century made wide use of the epistemological model of the fluid in the course of their answers to the expectations of socio-economic milieux of their time. In the field of locomotion and motor, steam was the energy of power, heavy and dangerous, and electricity was the new universal energy promised to success. The military engineer Arthur Krebs, looking for the control of matter and energy, has designed innovative electrical objects of aerostatic and underwater mobility considered as continuous sets of collected fluids, transported. The young Republic of France in reconstruction had dreams of modernity and autonomy. The engineer reorganizing the Fire Department of the City of Paris, no longer only had to control the material fluids; he also had to control the time-fluid, as invisible as the electric fluid was. The mechanical and electrical speed was his answer to fluidity requirements. The thought of mobility, speed and autonomy ultimately lead Arthur Krebs to promote, while working at Panhard-Levassor’s, the automotive and oil choices by providing technical solutions in the way of hybridization oil and electricity, so that people said that the electricity had “saved” the gasoline engine in front of the steam and electric engines

IL-33 biology in cancer: An update and future perspectives.

Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is constitutively expressed in the nucleus of epithelial, endothelial and fibroblast-like cells. Upon cell stress, damage or necrosis, IL-33 is released into the cytoplasm to exert its prime role as an alarmin by binding to its specific receptor moiety, ST2. IL-33 exhibits pleiotropic function in inflammatory diseases and particularly in cancer. IL-33 may play a dual role as both a pro-tumorigenic and anti-tumorigenic cytokine, dependent on tumor and cellular context, expression levels, bioactivity and the nature of the inflammatory environment. In this review, we discuss the differential contribution of IL-33 to malignant or inflammatory conditions, its multifaceted effects on the tumor microenvironment, while providing possible explanations for the discrepant findings described in the literature. Additionally, we examine the emerging and divergent functions of IL-33 in the nucleus, and aspects of IL-33 biology that are currently under-addressed

The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment

There is compelling evidence that inflammation contributes to tumorigenesis. Inflammatory mediators within the tumor microenvironment can either promote an antitumor immune response or support tumor pathogenesis. Therefore, it is critical to determine the relative contribution of tumor-associated inflammatory pathways to cancer development. Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is released upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of type-2 immune responses. However, recent findings have shown a role of IL-33 in several cancers where it may exert multiple functions. In this review, we will present the current knowledge on the role of IL-33 in the microenvironment of different tumors. We will highlight which cells produce and which cells are activated by IL-33 in cancer. Furthermore, we will explain how IL-33 modulates the tumor-associated inflammatory microenvironment to restrain or promote tumorigenesis. Finally, we will discuss the issues to be addressed first before potentially targeting the IL-33 pathway for cancer therapy

Molecular Characterization of Virus-induced Autoantibody Responses

Here we present a comprehensive molecular mapping of virus-induced autoimmune B cell responses obtained by serological identification of antigens by recombinant expression cloning analysis. Immunoscreening of cDNA expression libraries of various organs (lung, liver, and spleen) using sera from mice infected with cytopathic (vaccinia virus [VV]) or noncytopathic (lymphocytic choriomeningitis virus [LCMV]) viruses revealed a broad specificity of the elicited autoantibody response. Interestingly, the majority of the identified autoantigens have been previously described as autoantigens in humans. We found that induction of virus-induced autoantibodies of the immunoglobulin G class largely depends on the CD40–CD40L-mediated interaction between T and B cells. Furthermore, antibody titers against a number of autoantigens were comparable to the concomitantly induced antiviral antibody response. Comparison of serum reactivity against a selected panel of autoantigens after infection with VV, LCMV, or vesicular stomatitis virus showed that the different virus infections triggered distinct autoantibody responses, suggesting that virus infections may leave specific “autoantibody fingerprints” in the infected host

Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection

Plasmacytoid dendritic cells (pDCs) are the major producers of type I IFN in response to viral infection and have been shown to direct both innate and adaptive immune responses in vitro. However, in vivo evidence for their role in viral infection is lacking. We evaluated the contribution of pDCs to acute and chronic virus infection using the feeble mouse model of pDC functional deficiency. We have previously demonstrated that feeble mice have a defect in TLR ligand sensing. Although pDCs were found to influence early cytokine secretion, they were not required for control of viremia in the acute phase of the infection. However, T cell priming was deficient in the absence of functional pDCs and the virus-specific immune response was hampered. Ultimately, infection persisted in feeble mice. We conclude that pDCs are likely required for efficient T cell priming and subsequent viral clearance. Our data suggest that reduced pDC functionality may lead to chronic infection

Inositol Phosphatase SHIP1 – a Regulator of Osteoclast Lineage Cell Development and Activity

Introduction: Src-homology (SH) 2 domain-containing inositol-5-phosphatase 1 (SHIP1) is a negative regulator of the PI3K/Akt pathway that is expressed in hematopoietic cells. Osteoclast (OC) development depends on two essential pathways activated by receptor activator of NF-κB ligand (RANKL) and colony-stimulating factor-1 (CSF-1). Both pathways involve PI3K in their signalling and may therefore be regulated by SHIP1. SHIP1-deficient mice ((SHIPstyx/styx) are characterized by low bone density that has been suggested to be caused by an increased number of hyperactive OC. Purpose: This study aimed to investigate cellular mechanisms leading to low bone mass in SHIP1-deficient mice. Methods: MicroCT analysis of vertebrae and femora was performed to evaluate bone structure in vivo. To study OC development in vitro, progenitor cells (OPC) from SHIP1-deficient SHIPstyx/styx and control mice were cultured with RANKL and CSF-1. Osteoclastogenesis was assessed using an XTT cell viability assay and by determining TRAP activity. Furthermore, the capacity of OC to dissolve amorphous calcium phosphate (CaP) was determined. Results: In vivo, BV/TV of vertebrae and femora of SHIPstyx/styx mice was decreased compared to wt animals (40% and 35%, respectively, p<0.01). Trabecular number in vertebrae from SHIPstyx/styx mice was increased by 26%, while thickness was decreased by 30% (p<0.01). In femora from SHIPstyx/styx, trabecular thickness was reduced by 25% (p<0.05), whereas trabecular number remained unchanged. In vitro, SHIPstyx/styx OPC showed a 1.5-fold increased proliferation compared to controls (p<0.001), yet the number of OPC-derived OC was reduced by 40%. The capacity of SHIPstyx/styx OC to dissolve CaP was decreased by 60% compared to controls (p<0.001). Conclusions: Our data indicates a central role for SHIP1 in OC development and activity in vitro. The low bone mass phenotype in SHIPstyx/styx mice, however, may be caused by reduced bone formation or by the wasting disease and systemic inflammatory condition characteristic of SHIP1-deficient mice

The inositol phosphatase SHIP1 regulates skeletal development

Background/Introduction: Src-homology (SH) 2 domain-containing inositol-5-phosphatase 1 (SHIP1) is a lipid phosphatase expressed mainly in hematopoietic cells. SHIP1 regulates cell proliferation, differentiation, and survival via the PI3K/Akt signaling pathway. SHIP1-deficient (Styx) mice are osteoporotic, which is associated with an increased number of osteoclasts (OC). Purpose: This study aimed to investigate the underlying mechanisms through which SHIP1 controls osteoporosis. Methods: Osteoclast progenitor cells (OPC) were generated by incubating bone marrow cells with CSF-1. To develop OC, OPC from Styx, Styx het (heterozygous) and wt (wild type) mice were cultured with RANKL and CSF-1. Osteoclastogenesis was evaluated using an XTT cell viability assay, TRAP activity (OC marker) and qRT-PCR. Micro-computed tomography (Micro-CT) of vertebrae and femora were performed to evaluate the bone structure. Results: Deficiency in SHIP1 affected several aspects of bone. Compared to Styx het and wt controls, OPC-derived Styx OC presented several developmental defects, including a lower TRAP/XTT ratio and a 52% decrease in Calcr transcripts (encoding for the Calcitonin Receptor) (p<0.001). In vivo, there was a strong reduction of BV/TV in vertebrae and femora of Styx versus wt animals (39.6% and 35%, respectively, p<0.01). In particular, trabeculae in Styx vertebrae were increased by 8% (p<0.05) in numbers while decreased by 37% in thickness (p<0.001). In contrast, in Styx femora both the number and thickness of the trabeculae were decreased by 16% and 14%, respectively. These different phenotypes in Styx femora versus vertebrae indicate different paths to osteoporosis in bones with primary or secondary spongiosa. Conclusion(s): Taken together, our data indicate a central role for SHIP1-dependent PI3K/Akt signalling in bone remodeling. Further investigation will address the role of osteoblasts in the development of osteoporosis in SHIP1-deficient Styx mice

Immune cell extravasation in an organ-on-chip to model lung inflammation.

Acute respiratory distress syndrome (ARDS) is a severe lung condition with high mortality and various causes, including lung infection. No specific treatment is currently available and more research aimed at better understanding the pathophysiology of ARDS is needed. Most lung-on-chip models that aim at mimicking the air-blood barrier are designed with a horizontal barrier through which immune cells can migrate vertically, making it challenging to visualize and investigate their migration. In addition, these models often lack a barrier of natural protein-derived extracellular matrix (ECM) suitable for live cell imaging to investigate ECM-dependent migration of immune cells as seen in ARDS. This study reports a novel inflammation-on-chip model with live cell imaging of immune cell extravasation and migration during lung inflammation. The three-channel perfusable inflammation-on-chip system mimics the lung endothelial barrier, the ECM environment and the (inflamed) lung epithelial barrier. A chemotactic gradient was established across the ECM hydrogel, leading to the migration of immune cells through the endothelial barrier. We found that immune cell extravasation depends on the presence of an endothelial barrier, on the ECM density and stiffness, and on the flow profile. In particular, bidirectional flow, broadly used in association with rocking platforms, was found to importantly delay extravasation of immune cells in contrast to unidirectional flow. Extravasation was increased in the presence of lung epithelial tissue. This model is currently used to study inflammation-induced immune cell migration but can be used to study infection-induced immune cell migration under different conditions, such as ECM composition, density and stiffness, type of infectious agents used, and the presence of organ-specific cell types