Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of cortistatin on the production of inflammatory mediators and its therapeutic action in various murine models of endotoxemia. Cortistatin down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of cortistatin protected against lethality after cecal ligation and puncture, or injection of bacterial endotoxin or Escherichia coli, and prevented the septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascular disseminated coagulation in various target organs. The therapeutic effect of cortistatin was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and acute phase proteins. The combined use of cortistatin and other antiinflammatory peptides was very efficient treating murine septic shock. This work provides the first evidence of cortistatin as a new immunomodulatory factor with the capacity to deactivate the inflammatory response. Cortistatin represents a potential multistep therapeutic agent for human septic shock, to be used in combination with other immunomodulatory agents or as a complement to other therapies

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

© 2016 Chorny et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation-related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell-independent and T cell-dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.This study was supported by European Advanced grant ERC-2011-ADG-20110310, Ministerio de Ciencia e Innovación grant SAF2011-25241, and Marie Curie reintegration grant PIRG-08-GA-2010-276928 to A. Cerutti; Sara Borrell post-doctoral fellowships to A. Chorny; and US National Institutes of Health grants R01 AI57653, U01 AI95613, P01 AI61093, and U19 096187 to A. Cerutti. C. Cunha and A. Carvalho were funded by grants from Fundação para a Ciência e Tecnologia, co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte)., and from the Quadro de Referência Estratégico Nacional (SFRH/BPD/96176/2013 to C. Cunha and grant IF/00735/2014 to A. Carvalho) through the Fundo Europeu de Desenvolvimento Regional and Projeto Estratégico (LA 26 – 2013–2014; PEst-C/SAU/LA0026/2013). The financial support of the European Commission (FP7-HEALTH-2011-ADITEC-No.280873 and ERC-PHII-669415) to A. Mantovani is gratefully acknowledged.info:eu-repo/semantics/publishedVersio

The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells

Pentraxin 3 (PTX3) is a fluid-phase pattern recognition receptor of the humoral innate immune system with ancestral antibody-like properties but unknown antibody-inducing function. In this study, we found binding of PTX3 to splenic marginal zone (MZ) B cells, an innate-like subset of antibody-producing lymphocytes strategically positioned at the interface between the circulation and the adaptive immune system. PTX3 was released by a subset of neutrophils that surrounded the splenic MZ and expressed an immune activation–related gene signature distinct from that of circulating neutrophils. Binding of PTX3 promoted homeostatic production of IgM and class-switched IgG antibodies to microbial capsular polysaccharides, which decreased in PTX3-deficient mice and humans. In addition, PTX3 increased IgM and IgG production after infection with blood-borne encapsulated bacteria or immunization with bacterial carbohydrates. This immunogenic effect stemmed from the activation of MZ B cells through a neutrophil-regulated pathway that elicited class switching and plasmablast expansion via a combination of T cell–independent and T cell–dependent signals. Thus, PTX3 may bridge the humoral arms of the innate and adaptive immune systems by serving as an endogenous adjuvant for MZ B cells. This property could be harnessed to develop more effective vaccines against encapsulated pathogens.European Advanced grant ERC-2011-ADG-20110310, Ministerio de Ciencia e Innovación grant SAF2011-25241, and Marie Curie reintegra -tion grant PIRG-08-GA-2010-276928 to A. Cerutti; Sara Borrell post-doctoral fellow -ships to A. Chorny; and US National Institutes of Health grants R01 AI57653, U01 AI95613, P01 AI61093, and U19 096187 to A. Cerutti. C. Cunha and A. Carvalho were funded by grants from Fundação para a Ciência e Tecnologia, co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte)., and from the Quadro de Referência Estratégico Nacional (SFRH/BPD/96176/2013 to C. Cunha and grant IF/00735/2014 to A. Carvalho) through the Fundo Europeu de Desenvolvimento Regional and Projeto Estratégico (LA 26 – 2013–2014; PEst-C/SAU/LA0026/2013

Efecto de neuropéptidos en el restablecimiento de la homeostasis en inflamación y autoinmunidad

Tesis Univ. Granada. Departamento de Bioquímica y Biología Molecular III e Inmunología. Leída el 25 de junio de 200

Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1

Originally described as a nuclear protein that bends DNA, the high mobility group box 1 protein (HMGB1) has recently emerged as a necessary and sufficient late mediator of severe sepsis. HMGB1 is therefore a molecular target that provides a wide window for clinical intervention in sepsis. Vasoactive intestinal peptide (VIP) and urocortin are two well known anti-inflammatory neuropeptides that protect against several immune disorders by regulating a wide panel of inflammatory mediators. In this study, we demonstrate the therapeutic effect of VIP and urocortin in various models of established sepsis: both agents reduced lethality induced by cecal ligation and puncture or by injection of live Escherichia coli. The therapeutic effect of VIP and urocortin was accompanied by a decrease in systemic levels of HMGB1. In addition, administration of recombinant HMGB1 completely reversed the protective effect of VIP and urocortin in experimental sepsis. In vitro and ex vivo studies show that both VIP and urocortin down-regulate translocation of HMGB1 from the nucleus to the cytoplasm and its subsequent secretion by activated macrophages, suggesting that macrophages are major targets in the inhibitory activity of these neuropeptides. To our knowledge, VIP and urocortin are the first endogenous inhibitors of HMGB1 secretion shown to improve sepsis survival in a clinically relevant time frame. Copyright © American Society for Investigative Pathology.Peer Reviewe

Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells

Rheumatoid arthritis is a chronic autoimmune disease of unknown etiology characterized by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. The present study proposes a new strategy for the treatment of arthritis: the administration of the immunomodulatory neuropeptide adrenomedullin. Treatment with adrenomedullin significantly reduced incidence and severity of collagen-induced arthritis, an experimental model of rheumatoid arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of adrenomedullin was associated with a striking reduction of the two deleterious components of the disease, ie, the Th1-driven autoimmune and inflammatory responses. Adrenomedullin also induced the generation and/or activation of efficient CD4+CD25+ regulatory T cells in arthritis with capacity to suppress autoreactive response and restore immune tolerance, which could play a pivotal role in the therapeutic effect of adrenomedullin on experimental arthritis contributing to the restoration of immune tolerance. Copyright © American Society for Investigative Pathology.Peer Reviewe

Tuning inflammation with anti-inflammatory neuropeptides

The immune system is confronted with the daunting task of defending the organism against invading pathogens while at the same time remaining self-tolerant to the body's own constituents and preserving its integrity. The loss of immune tolerance stemming from an unbalance in pro-inflammatory factors versus anti-inflammatory cytokines, or of autoreactive/inflammatory T helper 1 cells versus regulatory/suppressive T cells, results in the breakdown of immune homeostasis and the subsidiary appearance of exacerbated inflammatory and autoimmune diseases. Some neuropeptides have been shown to have anti-inflammatory properties and to participate in maintaining immune tolerance. Here the authors examine the most recent developments in this field and highlight the effectiveness of using neuropeptides in treating several inflammatory and autoimmune disorders. © 2007 Informa UK Ltd.Peer Reviewe

Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria

Sepsis, a life-threatening complication of infections and the most common cause of death in intensive care units, is characterized by a hyperactive and out-of-balance network of endogenous proinflammatory cytokines. None of the current therapies are entirely effective, illustrating the need for novel therapeutic approaches. Ghrelin (GHR) is an orexigenic peptide that has emerged as a potential endogenous anti-inflammatory factor. In this study, we show that the delayed administration of GHR protects against the mortality in various models of established endotoxemia and sepsis. The therapeutic effect of GHR is mainly mediated by decreasing the secretion of the high mobility box 1 (HMGB1), a DNA-binding factor that acts as a late inflammatory factor critical for sepsis progression. Macrophages seem to be the major cell targets in the inhibition of HMGB1 secretion, in which GHR blocked its cytoplasmic translocation. Interestingly, we also report that GHR shows a potent antibacterial activity in septic mice and in vitro. Remarkably, GHR also reduces the severity of experimental arthritis and the release of HMGB1 to serum. Therefore, by regulating crucial processes of sepsis, such as the production of early and late inflammatory mediators by macrophages and the microbial load, GHR represents a feasible therapeutic agent for this disease and other inflammatory disorders. Copyright © 2008 by The American Association of Immunologists, Inc.Peer Reviewe

Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells

Objective. To investigate the potential therapeutic action of the immunomodulatory neuropeptide urocortin (UCN) in an experimental model of rheumatoid arthritis (RA). Methods. After disease onset, DBA/1J mice with collagen-induced arthritis (CIA) were treated with UCN, and the incidence, severity (clinical score), and joint histopathology were evaluated. The inflammatory response was determined by measuring the levels of different mediators of inflammation (cytokines and chemokines) in the joints and sera. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen and by assaying the content of serum autoantibodies. The number of regulatory CD4+,CD25+ T cells and their capacity to suppress self-reactive Th1 cells were determined in joints and lymph nodes. Results. UCN treatment significantly reduced the incidence and severity of CIA, completely abrogating joint swelling and cartilage and bone destruction. The therapeutic effect of UCN was associated with a striking reduction of the 2 deleterious components of the disease: the Th1-driven autoimmune response and the inflammatory response. UCN also induced the generation and/or activation of efficient interleukin-10/transforming growth factor β1-producing Treg cells in arthritis with the capacity to suppress the autoreactive response and to restore immune tolerance, thus playing a pivotal role in the therapeutic effect of UCN. Conclusion. Our findings provide a powerful rationale for assessing the efficacy of UCN as a novel multistep therapeutic approach to the treatment of RA in humans. © 2007, American College of Rheumatology.Peer Reviewe