Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18.
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.
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.edu.
James Lawrence
JL
Wynn
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232;
Chris S
CS
Wilson
Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232;
Jacek
J
Hawiger
Division of Dermatology, University of California, Los Angeles, CA 90095;
Philip O
PO
Scumpia
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
Andrew F
AF
Marshall
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
Jin-Hua
JH
Liu
Department of Pediatrics, University of Florida, Gainesville, FL 32610;
Irina
I
Zharkikh
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
Hector R
HR
Wong
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
Patrick
P
Lahni
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
John T
JT
Benjamin
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
Erin J
EJ
Plosa
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
Jörn-Hendrik
JH
Weitkamp
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232;
Edward R
ER
Sherwood
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Lyle L
LL
Moldawer
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
Ricardo
R
Ungaro
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610;
Henry V
HV
Baker
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610;
M Cecilia
MC
Lopez
Department of Pediatrics, University of Iowa, Iowa City, IA 52242;
Steven J
SJ
McElroy
Center for Inflammation & Mucosal Immunology, University of Florida, Gainesville, FL 32610.
Natacha
N
Colliou
Center for Inflammation & Mucosal Immunology, University of Florida, Gainesville, FL 32610.
Mansour
M
Mohamadzadeh
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
Daniel Jensen
DJ
Moore
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D005260:Female; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D020382:Interleukin-18 / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D000071074:Neonatal Sepsis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D020382:Interleukin-18
IL-17; IL-18; neonate; pathogenesis; sepsis