scholarly journals N-chlorination mediates protective and immunomodulatory effects of oxidized human plasma proteins

2019 ◽  
Author(s):  
Agnes Ulfig ◽  
Anton V. Schulz ◽  
Alexandra Müller ◽  
Natalie Lupilov ◽  
Lars I. Leichert
Keyword(s):  
Immune Cells ◽  
Plasma Proteins ◽  
Feedback Loop ◽  
Hypochlorous Acid ◽  
Basic Amino Acid ◽  
Immunomodulatory Effects ◽  
Positive Feedback Loop ◽  
Amino Acid Side Chains ◽  
Blood Plasma Proteins ◽  
Reversible Nature

ABSTRACTHypochlorous acid (HOCl), a powerful antimicrobial oxidant, is produced by neutrophils to fight infections. Here we show thatN-chlorination, induced by HOCl concentrations encountered at sites of inflammation, converts blood plasma proteins into chaperone-like holdases that protect other proteins from aggregation. This chaperone-like conversion was reversible by antioxidants and was abrogated by prior methylation of basic amino acids. Furthermore, reversibleN-chlorination of basic amino acid side chains is the major factor that converts plasma proteins into efficient activators of immune cells. Finally, HOCl-modified serum albumin was found to act as a pro-survival molecule that protects neutrophils from cell death induced by highly immunogenic foreign antigens. We propose that activation and enhanced persistence of neutrophils mediated by HOCl-modified plasma proteins, resulting in the increased and prolonged generation of ROS, including HOCl, constitutes a potentially detrimental positive feedback loop that can only be attenuated through the reversible nature of the modification involved.

scholarly journals N-chlorination mediates protective and immunomodulatory effects of oxidized human plasma proteins

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Agnes Ulfig ◽  
Anton V Schulz ◽  
Alexandra Müller ◽  
Natalie Lupilov ◽  
Lars I Leichert
Keyword(s):  
Immune Cells ◽  
Plasma Proteins ◽  
Feedback Loop ◽  
Hypochlorous Acid ◽  
Basic Amino Acid ◽  
Immunomodulatory Effects ◽  
Positive Feedback Loop ◽  
Amino Acid Side Chains ◽  
Blood Plasma Proteins ◽  
Reversible Nature

Hypochlorous acid (HOCl), a powerful antimicrobial oxidant, is produced by neutrophils to fight infections. Here, we show that N-chlorination, induced by HOCl concentrations encountered at sites of inflammation, converts blood plasma proteins into chaperone-like holdases that protect other proteins from aggregation. This chaperone-like conversion was reversible by antioxidants and was abrogated by prior methylation of basic amino acids. Furthermore, reversible N-chlorination of basic amino acid side chains is the major factor that converts plasma proteins into efficient activators of immune cells. Finally, HOCl-modified serum albumin was found to act as a pro-survival molecule that protects neutrophils from cell death induced by highly immunogenic foreign antigens. We propose that activation and enhanced persistence of neutrophils mediated by HOCl-modified plasma proteins, resulting in the increased and prolonged generation of ROS, including HOCl, constitutes a potentially detrimental positive feedback loop that can only be attenuated through the reversible nature of the modification involved.

scholarly journals Interleukin 6 in inflammation, autoimmunity and cancer

2020 ◽  
Author(s):  
Toshio Hirano
Keyword(s):  
Chronic Inflammation ◽  
Immune Cells ◽  
Positive Feedback ◽  
Interleukin 6 ◽  
Feedback Loop ◽  
Inflammatory Responses ◽  
Virus Disease ◽  
Cytokine Storm ◽  
Necrosis Factor Alpha ◽  
Positive Feedback Loop

Abstract Interleukin 6 (IL-6) is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune cells and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is a NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6–STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6–STAT3 axis is a critical target for treating diseases.

scholarly journals Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Geneviève Pépin ◽  
Dominic De Nardo ◽  
Christina L. Rootes ◽  
Tomalika R. Ullah ◽  
Sumaiah S. Al-Asmari ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cyclic Gmp ◽  
Immune Cells ◽  
Feedback Loop ◽  
Direct Evidence ◽  
Critical Role ◽  
Positive Feedback Loop ◽  
Dna Viruses ◽  
Antiviral Responses ◽  
Infected Cells

ABSTRACT Activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in antiviral responses to many DNA viruses. Sensing of cytosolic DNA by cGAS results in synthesis of the endogenous second messenger cGAMP that activates stimulator of interferon genes (STING) in infected cells. Critically, cGAMP can also propagate antiviral responses to uninfected cells through intercellular transfer, although the modalities of this transfer between epithelial and immune cells remain poorly defined. We demonstrate here that cGAMP-producing epithelial cells can transactivate STING in cocultured macrophages through direct cGAMP transfer. cGAMP transfer was reliant upon connexin expression by epithelial cells and pharmacological inhibition of connexins blunted STING-dependent transactivation of the macrophage compartment. Macrophage transactivation by cGAMP contributed to a positive-feedback loop amplifying antiviral responses, significantly protecting uninfected epithelial cells against viral infection. Collectively, our findings constitute the first direct evidence of a connexin-dependent cGAMP transfer to macrophages by epithelial cells, to amplify antiviral responses. IMPORTANCE Recent studies suggest that extracellular cGAMP can be taken up by macrophages to engage STING through several mechanisms. Our work demonstrates that connexin-dependent communication between epithelial cells and macrophages plays a significant role in the amplification of antiviral responses mediated by cGAMP and suggests that pharmacological strategies aimed at modulating connexins may have therapeutic applications to control antiviral responses in humans.

scholarly journals Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

2020 ◽  
Vol 21 (17) ◽  
pp. 6009
Author(s):  
Valerio Gelfo ◽  
Donatella Romaniello ◽  
Martina Mazzeschi ◽  
Michela Sgarzi ◽  
Giada Grilli ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Immune Cells ◽  
Feedback Loop ◽  
Innate Immune ◽  
Critical Function ◽  
Positive Feedback Loop ◽  
Pathological Conditions ◽  
Cancer Initiation

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

Post-Translational Oxidation Modifications of Blood Plasma Proteins of Cosmonauts after a Long-term Flight: Part I

2020 ◽  
Vol 46 (5) ◽  
pp. 531-539
Author(s):  
I. M. Larina ◽  
A. G. Brzhzovsky ◽  
A. M. Nosovsky ◽  
A. S. Kononikhin ◽  
O. I. Orlov
Keyword(s):  
Blood Plasma ◽  
Plasma Proteins ◽  
Blood Plasma Proteins
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