title: High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates.
abstract: The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
authors: Thierry
authors: http://orcid.org/0000-0002-9358-0109
authors: T
authors: Roger
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Neonatology, Department of Pediatrics, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
authors: Anina
authors: A
authors: Schneider
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Neonatology, Department of Pediatrics, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
authors: Manuela
authors: M
authors: Weier
authors: Department of Laboratory Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands;
authors: Fred C G J
authors: FC
authors: Sweep
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
authors: Didier
authors: D
authors: Le Roy
authors: Institute of Biochemistry and Molecular Cell Biology, Rheinisch-Westfälisch Technische Hochschule Aachen University, D-52074 Aachen, Germany; Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University, D-81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), D-81377 Munich, Germany.
authors: Jürgen
authors: J
authors: Bernhagen
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
authors: Thierry
authors: T
authors: Calandra
authors: Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Neonatology, Department of Pediatrics, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Eric.Giannoni@chuv.ch.
authors: Eric
authors: E
authors: Giannoni
mesh_terms: D000328:Adult; D000818:Animals; D004926:Escherichia coli / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007231:Infant, Newborn; D019746:Intramolecular Oxidoreductases / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000276:immunology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse
keywords: Escherischia coli; adenosine; newborns; prostaglandin; sepsis