IFN neutralization prevented lung infection-induced bone marrow depression in type-I-IFN-receptor-deficient (IFNAR?/?) mice, and prolonged neutrophil survival time in bone marrow from IFrag?/? mice

IFN neutralization prevented lung infection-induced bone marrow depression in type-I-IFN-receptor-deficient (IFNAR?/?) mice, and prolonged neutrophil survival time in bone marrow from IFrag?/? mice. prolonged neutrophil survival time in bone marrow from IFrag?/? mice. IL-1 and upstream regulators of IFN, IL-12 and IL-18, were also upregulated in lung and serum of IFrag?/? mice. In conjunction there was exuberant inflammasome-mediated caspase-1-activation in pulmonary innate immune cells required for processing of IL-18 and IL-1. Thus, absence of type-I-IFN-signaling during lung infection may result in deregulation of inflammasome-mediated pulmonary immune activation causing systemic immune deviations triggering BMF in this model. Introduction Bone marrow Mouse monoclonal to GFP failure can occur in the context of inherited and acquired conditions and manifests in its extreme form as aplastic anemia with severe peripheral cytopenias and acellular bone marrow spaces (1). While most acquired aplastic anemias Atropine are thought to be the result of an T cell mediated autoimmune response to an unknown, likely infectious trigger, inherited forms are defined by gene defects often affecting the viability of hematopoietic stem cells in response to inflammatory stimuli (2-5). Furthermore, peripheral cytopenias due to bone marrow suppression can also occur as a complication of severe inflammatory syndromes such as rheumatoid diseases, severe sepsis and AIDS (6-8). Thus, while pathomechanistically complex and multifactorial, a common theme appears to be the presence of inflammatory stimuli accompanied by immune deviations. is an extracellular, opportunistic fungal pathogen of the lung that causes a life threatening pneumonia in severely immune compromised individuals with e.g HIV infection or immunosuppressive therapy (9). Although the infection often resolves unnoticed in otherwise healthy individuals, there is increasing evidence that low grade pulmonary colonization/infection can exacerbate the symptoms of chronic pulmonary diseases such as COPD (10, 11) and thus may also exacerbate systemic complications associated with it (12). As with many other fungal pathogens, immune protection from infection critically depends on CD4-T cell mediated immune responses (13, 14). However, while immunity to many other pulmonary fungal pathogens appears to involve inflammasome-mediated immune-activation following innate pattern recognition and activation of a Th-1/TH-17-driven adaptive immune response (15, 16), there is increasing evidence that successful immunity to lung infection involves TH-2-mediated immune responses including alternative macrophage activation and B cell-mediated clearance (17-22). Type-I-IFNs have long been known as antiviral (reviewed in (23)), and their role as mediators of immunity to bacterial and some fungal infections has just been recognized (reviewed in (24, 25). Type-I-IFNs activate macrophages, promote DC maturation, enhance TH-1-and NK-cell-mediated immunity (26-28) but also support B cell-differentiation to antibody-secreting plasma cells (29). While type-I-IFN-mediated responses have been implicated in immune-mediated damage to specific pathogens (30) and autoimmune diseases (31, 32), they are also immune modulators. In this regard, type-I-IFNs induce IL-10 production in LPS stimulated macrophages (33) and in antigen-specific T cells leading to the suppression of a Th17-associated autoimmune inflammation in a mouse model of multiple sclerosis (MS) (34, 35). In addition, type-I-IFNs induce transcriptional repression of TNF- (36), inhibition of inflammasome activation and subsequent IL-1 processing (37), and are thus therapeutically utilized in patients with MS (38-40) and evaluated for patients with chronic inflammatory bowel Atropine diseases (41-43). Therefore, type-I-IFNs are pleiotropic and their Atropine activity is likely dose-dependent and determined by the immunological microenvironment. Indeed, low amounts of IFN- accumulate in tissue in the absence of infection maintaining a wide variety of signaling molecules important for Atropine immunity and tissue homeostasis (44). While Atropine in high dosages myelosuppressive (45, 46), type-I-IFNs act as neutrophil survival factors similar to G-CSF (47). Furthermore, type-I-IFNs are critical regulators of bone homeostasis (reviewed in (48, 49)) and thus may also protect the bony hematopoietic stem cell niche and hematopoiesis (50, 51). However, excessive IFN production during inflammatory responses can also induce and exhaust the proliferative capacity of the hematopoietic stem cell (HSC) and impact self renewal (52). The.

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