Journal article
Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18
Proceedings of the National Academy of Sciences - PNAS, Vol.113(19), pp.E2627-E2635
05/10/2016
DOI: 10.1073/pnas.1515793113
PMCID: PMC4868456
PMID: 27114524
Abstract
Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G(+) myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.
Details
- Title: Subtitle
- Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18
- Creators
- James Lawrence Wynn - Department of Pediatrics, University of Florida, Gainesville, FL 32610; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610; james.wynn@peds.ufl.eduSteven J McElroy - Department of Pediatrics, University of Iowa, Iowa City, IA 52242Chris S Wilson - Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232Jacek Hawiger - Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232Philip O Scumpia - Division of Dermatology, University of California, Los Angeles, CA 90095Andrew F Marshall - Department of Pediatrics, Vanderbilt University, Nashville, TN 37232Jin-Hua Liu - Department of Pediatrics, Vanderbilt University, Nashville, TN 37232Irina Zharkikh - Department of Pediatrics, University of Florida, Gainesville, FL 32610Hector R Wong - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229Patrick Lahni - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229John T Benjamin - Department of Pediatrics, Vanderbilt University, Nashville, TN 37232Erin J Plosa - Department of Pediatrics, Vanderbilt University, Nashville, TN 37232Jörn-Hendrik Weitkamp - Department of Pediatrics, Vanderbilt University, Nashville, TN 37232Edward R Sherwood - Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232Lyle L Moldawer - Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610Ricardo Ungaro - Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610Henry V Baker - Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610M Cecilia Lopez - Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610Natacha Colliou - Center for Inflammation & Mucosal Immunology, University of Florida, Gainesville, FL 32610Mansour Mohamadzadeh - Center for Inflammation & Mucosal Immunology, University of Florida, Gainesville, FL 32610Daniel Jensen Moore - Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Pediatrics, Vanderbilt University, Nashville, TN 37232
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.113(19), pp.E2627-E2635
- DOI
- 10.1073/pnas.1515793113
- PMID
- 27114524
- PMCID
- PMC4868456
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- K08 DK090146 / NIDDK NIH HHS L40 DK084746 / NIDDK NIH HHS I01 BX002750 / BLRD VA K08 HL127102 / NHLBI NIH HHS T32 GM008554 / NIGMS NIH HHS K08 GM106143 / NIGMS NIH HHS F31 DK107321 / NIDDK NIH HHS R25 GM062459 / NIGMS NIH HHS R01 GM097531 / NIGMS NIH HHS R03 DK097335 / NIDDK NIH HHS K08 HD061607 / NICHD NIH HHS R01 GM108025 / NIGMS NIH HHS L40 DK084865 / NIDDK NIH HHS
- Language
- English
- Date published
- 05/10/2016
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics
- Record Identifier
- 9984093227802771
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