Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in ...this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host-fungus interactions in mammals.
Endogenous tryptophan (Trp) metabolites have an important role in mammalian gut immune homeostasis, yet the potential contribution of Trp metabolites from resident microbiota has never been addressed ...experimentally. Here, we describe a metabolic pathway whereby Trp metabolites from the microbiota balance mucosal reactivity in mice. Switching from sugar to Trp as an energy source (e.g., under conditions of unrestricted Trp availability), highly adaptive lactobacilli are expanded and produce an aryl hydrocarbon receptor (AhR) ligand—indole-3-aldehyde—that contributes to AhR-dependent Il22 transcription. The resulting IL-22-dependent balanced mucosal response allows for survival of mixed microbial communities yet provides colonization resistance to the fungus Candida albicans and mucosal protection from inflammation. Thus, the microbiota-AhR axis might represent an important strategy pursued by coevolutive commensalism for fine tuning host mucosal reactivity contingent on Trp catabolism.
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•Lactobacilli switch from sugar to tryptophan in unrestricted tryptophan availability•Tryptophan degradation to indole derivatives activates AhR for IL-22 production•The AhR-IL-22 axis provides antifungal resistance and mucosal protection from damage•Dietary tryptophan affects host-fungal symbiosis via the microbiota
Epigenetic Mechanisms of Inflammasome Regulation Poli, Giulia; Fabi, Consuelo; Bellet, Marina Maria ...
International journal of molecular sciences,
08/2020, Letnik:
21, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The innate immune system represents the host's first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the ...activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.
The interrelationship between IgAs and microbiota diversity is still unclear. Here we show that BALB/c mice had higher abundance and diversity of IgAs than C57BL/6 mice and that this correlated with ...increased microbiota diversity. We show that polyreactive IgAs mediated the entrance of non-invasive bacteria to Peyer’s patches, independently of CX3CR1+ phagocytes. This allowed the induction of bacteria-specific IgA and the establishment of a positive feedback loop of IgA production. Cohousing of mice or fecal transplantation had little or no influence on IgA production and had only partial impact on microbiota composition. Germ-free BALB/c, but not C57BL/6, mice already had polyreactive IgAs that influenced microbiota diversity and selection after colonization. Together, these data suggest that genetic predisposition to produce polyreactive IgAs has a strong impact on the generation of antigen-specific IgAs and the selection and maintenance of microbiota diversity.
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•Different mouse strains have diverse predisposition to produce innate IgAs•Innate IgAs allow a controlled bacterial entrance•IgA-coated bacteria initiate a positive feedback loop of IgA production•IgA diversity results in microbiota diversification
Reduced microbiota diversity has been associated with several pathologic conditions. Rescigno et al. show that the capacity to produce innate IgAs has an impact on microbiota diversity. IgAs can mediate the internalization of non-invasive bacteria and the initiation of a positive feedback loop of IgA production. IgA diversity might be a marker of a healthy condition.
The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that ...regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 5'-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes.
Background
Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer‐associated deaths, is still a poorly understood process ...without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end‐products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer.
Methods
By using murine models consisting in the injection of colon 26 murine adenocarcinoma (C26‐ADK) or Lewis lung carcinoma (LLC) cells in BALB/c and C57BL/6 or Ager−/− (RAGE‐null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state. In vitro experiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL/6 wild type and Ager−/− mice treated with the RAGE ligand, S100B (S100 calcium‐binding protein B), TNF (tumor necrosis factor)α±IFN (interferon) γ, and tumour cell‐ or masses‐conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type and Ager−/− mice were injected with TNFα/IFNγ or S100B in a tumour‐free environment.
Results
We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and/or tumour‐derived cachexia‐inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy per se via a p38 MAPK (p38 mitogen‐activated protein kinase)/myogenin axis and STAT3 (signal transducer and activator of transcription 3)‐dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour‐derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour‐derived pro‐cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia‐inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival.
Conclusions
RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome.
Patients with cystic fibrosis (PwCF) have recently experienced an unprecedented breakthrough with the adoption of modulator therapy in clinical practice. This remarkable achievement has led to the ...reconsideration of disease management as the increased life expectancy has gradually shifted the attention over a spectrum of extra-pulmonary manifestations that become prevalent in the aging population. It comes to be that complementary approaches that target patient co-morbidities are needed for the optimal clinical management of PwCF. A strategy would be to adjuvate the cystic fibrosis transmembrane conductance regulator (CFTR) in performing its functions in the different organs in which it is expressed. Solute carrier family 26 (SLC26) members appear ideal in this context. Indeed, they not only cooperate with CFTR in the organ-dependent regulation of ion fluxes but physically interact with it to reciprocally modulate their function. In this opinion, we summarize available evidence pointing to a physical and functional interaction between CFTR and SLC26 members, with a particular focus on SLC26A6 for its wider expression and broader anion selectivity, and then discuss how restoring the physical interaction between CFTR and SLC26A6 might be beneficial in the treatment of PwCF in the era of modulator therapy.
...of the impaired production of reactive oxygen species, patients with CGD often develop IA, typically within the first decade of life. ...a nonsynonymous polymorphism in human plasminogen was ...found to increase risk for IA in HSCT recipients, particularly late after transplantation.
Chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), ...is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood.
We found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47(phox-/-) mice and gp91(phox)-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kappaB activation, and elevated downstream pro-inflammatory cytokines (TNF-alpha, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kappaB activation.
These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD.
The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the ...development of invasive aspergillosis is unknown.
We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients.
Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus.
Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.).
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