The pituitary gland prevents shock-associated death by controlling multiple inflammatory mediators
Abstract Bacterial infections cause a major burden of disease worldwide. Sepsis and septic shock are life-threatening complications of infections. The hypothalamic-pituitary-adrenal (HPA) axis initiates the release of endogenous glucocorticoids that modulate the host stress response and acute inflammation during septic shock. It is an ongoing controversial debate, if therapeutic manipulations of the HPA axis could benefit the clinical situation in the context of shock. Here, we have studied Long Evans rats with hypophysectomy followed by endotoxic shock. The shock-associated lethality was substantially higher in hypophysectomized rats as compared to control mice after cranial sham surgery (…
Neutrophil extracellular traps impair fungal clearance in a mouse model of invasive pulmonary aspergillosis
Abstract Neutrophil extracellular traps (NETs) are formed by polymorphonuclear neutrophils (PMN) and contribute to the innate host defense by binding and killing bacterial and fungal pathogens. Because NET formation depends on histone hypercitrullination by peptidylarginine deiminase 4 (PAD4), we used PAD4 gene deficient (Pad4-/-) mice in a mouse model of invasive pulmonary aspergillosis (IPA) to address the contribution of NETs to the innate host defense in vivo. After the induction (24 h) of IPA by i.t. infection with Aspergillus fumigatus conidia, Pad4-/- mice revealed lower fungal burden in the lungs, accompanied by less acute lung injury, TNFα and citH3 compared to wildtype controls. T…
IL-27 enhances the lymphocyte mediated innate resistance to primary hookworm infection in the lungs
AbstractInterleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family, formed by non-covalent association of the promiscuous EBI3 subunit and selective p28 subunit. IL-27 is produced by mononuclear phagocytes and unfolds pleiotropic immune-modulatory functions through high affinity ligation to IL-27 receptor alpha (IL-27RA). While IL-27 is known to contribute to immunity and to end inflammation following numerous types of infections, its relevance for host defense against multicellular parasites is still poorly defined. Here, we investigated the role of IL-27 during infection with the soil-transmitted hookworm, Nippostrongylus brasiliensis, in its early intrapulmonary life cycle. I…
Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment
Abstract Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7–null mice) were almost completely resistant to CAC development. In patients with ulcerative c…
The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.
Significance: It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. Mitochondrial antiviral signaling protein (MAVS) is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation associated gene 5 (M…
Nanomedicine: A Diagnostic and Therapeutic Approach to COVID-19
The SARS-CoV-2 virus is causing devastating morbidity and mortality worldwide. Nanomedicine approaches have a high potential to enhance conventional diagnostics, drugs and vaccines. In fact, lipid nanoparticle/mRNA vaccines are already widely used to protect from COVID-19. In this review, we present an overview of the taxonomy, structure, variants of concern, epidemiology, pathophysiology and detection methods of SARS-CoV-2. The efforts of repurposing, tailoring, and adapting pre-existing medications to battle COVID-19 and the state of vaccine developments are presented. Next, we discuss the broad concepts and limitations of how nanomedicine could address the COVID-19 threat. Nanomaterials …