Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

Cuenca, Alex G.; Wynn, James L.; Kelly-Scumpia, Kindra M.; Scumpia, Philip O.; Vila, Lizette; Delano, Matthew J.; Mathews, Clayton E.; Wallet, Shannon M.; Reeves, Westley H.; Behrns, Kevin E.; Nacionales, Dina C.; Efron, Philip A.; Kunkel, Steven L.; Moldawer, Lyle L.

doi:10.1128/iai.01291-10

Cited by 39 publications

(45 citation statements)

References 28 publications

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“…2D) or function (phagocytosis/ROS production) of neonatal myeloid (CD11b + ) cells (Fig. 2E), which were predominantly PMNs (>80% Ly6G + CD11b + ), consistent with our previous report (19).…”

Section: Resultssupporting

confidence: 79%

“…Specific pathogen-free male and female C57BL/6 mice (WT and genetically modified) between 6 and 8 wk of age were purchased from The Jackson Laboratory and were allowed to equilibrate to their environment for a minimum of 7 d before any breeding or experimental use. Pups aged 5-7 d (P5-7) were considered neonates (13,16,19,39). IL-1β −/− mice on a B6 background were the generous gift Scott Berceli (University of Florida, Gainesville, FL) and have been described previously (40).…”

Section: Methodsmentioning

confidence: 99%

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Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Wynn

Wilson

Hawiger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.IL-18 | IL-17 | sepsis | neonate | pathogenesis

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Section: Resultssupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Wynn

Wilson

Hawiger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore to address this, we utilized a cecal slurry model of peritonitis and sepsis to generate polymicrobial “hit”, previously reported by our group (2, 18). Surprisingly, no differences in survival were seen between TRIF −/− , MyD88 −/− , or WT animals in response to either an LD 40 or LD 70 of cecal slurry (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Peritoneal washes were harvested from neonates or adults via intraperitoneal injection of 500 µL or 5 mL of PBS at 4° C, respectively. Peritoneal washes and blood was then diluted and plated on blood agar plates (Fisher scientific) (18–20). …”

Section: Methodsmentioning

confidence: 99%

TRIF-Dependent Innate Immune Activation Is Critical for Survival to Neonatal Gram-Negative Sepsis

Cuenca

Joiner

Gentile

et al. 2015

The Journal of Immunology

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Current evidence suggests that neonatal immunity is functionally distinct from adults. Though toll like receptor (TLR) signaling through the adaptor protein, MyD88, has been shown to be critical for survival to sepsis in adults, little is known about the role of MyD88 or TRIF in neonatal sepsis. We demonstrate that TRIF−/− but not MyD88−/− neonates are highly susceptible to Escherichia coli peritonitis and bacteremia. This was associated with decreased innate immune recruitment and function. Importantly, we found that the reverse was true in adults, that MyD88−/−, but not TRIF−/− or wild-type adults are susceptible to E coli peritonitis and bacteremia. In addition, we demonstrate that TRIF but not MyD88 signaling is critical for the TLR4 protective adjuvant effect we have previously demonstrated. These data suggest a differential requirement for the survival of neonates versus adults to gram negative infection, and that modulation of TRIF in neonates can be used to augment survival to neonatal sepsis.

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“…We observed enhanced IL-10 production by L. major antigen-restimulated lymph node cells of infected BC CXCR3 Tg mice, which could explain the increased frequency of immature monocytes in these mice. This unexpected effect of transgenic T cell expression of CXCR3 on monocyte maturation during L. major infection expands our current understanding of the role of CXCR3 in macrophage function (47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 86%

Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response

et al. 2015

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e Cutaneous leishmaniasis, caused mainly by Leishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused by Leishmania major. Furthermore, T cells from L. major-susceptible BALB/c but not L. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance to L. major infection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes with L. major infection. Contrary to our hypothesis, transgenic expression of CXCR3 ( Leishmaniasis affects over 12 million people worldwide and, according to recent estimates, almost 2 million people are affected annually (1). It is therefore a major global health problem and has been classified by the World Health Organization as a neglected tropical disease. The most common form of the disease is cutaneous leishmaniasis (CL), which is caused by Leishmania major, Leishmania tropica, or Leishmania aethiopica in the Old World and by Leishmania mexicana species complex or Leishmania (Viannia) braziliensis species complex in the New World. CL is characterized by the development of large papular or nodular lesions at the infection site, which often become ulcerated and may persist for months or even years. In some patients, lesions can become chronic, leading to disfiguring mucosal leishmaniasis. There are currently no vaccines available for the disease, and resistance to first-line drugs is becoming increasingly common (2, 3).In murine models of CL, it is well established that protective host immunity depends on the generation and recruitment of appropriate Th1 immune cells to the site of infection. The hallmark of Th1 responses is the production of gamma interferon (IFN-␥), which activates mononuclear phagocytes, increases the production of reactive nitrogen species (RNS), and enhances parasite killing (4, 5). CXCR3 is a chemokine receptor which is preferentially expressed on Th1 cells and activated CD8 ϩ T cells and coordinates their recruitment to inflammatory sites where they exert their effector function. CXCR3 is regulated by the transcription factor T-bet, a master regulator of Th1 responses. CXCR3 has been shown to be important in immunity to intracellular parasites which require a Th1 immune response for protection, including L. major. Genetic deletion of cxcr3 in C57BL/6 (BL/6) mice, which are naturally resistant to L. major, renders them susceptible to localized infection. Although these mice are able to generate a Th1 immune response in the draining lymph nodes, they are unable to control parasite growth in the lesion due to defective CD4 ϩ and CD8 ϩ T cell migration to the site of infection (6). More recent studies have s...

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Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis

Cited by 39 publications

References 28 publications

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

TRIF-Dependent Innate Immune Activation Is Critical for Survival to Neonatal Gram-Negative Sepsis

Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response

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