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.2016 Aug;55(2):264-74.
doi: 10.1165/rcmb.2015-0380OC.

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

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Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

Adrian M Piliponsky et al. Am J Respir Cell Mol Biol.2016 Aug.

Abstract

The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for thymic stromal lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development.

Keywords: inflammation; myeloid cells; sepsis; thymic stromal lymphopoietin.

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Figures

Figure 1.
Figure 1.
Thymic stromal lymphopoietin (TSLP) levels are increased and improve survival after cecal ligation and puncture (CLP). (A andB) TSLP peritoneal lavage fluid (A) and plasma concentrations (B) at the indicated time points after induction of moderate CLP (50% ligation; single puncture with a 22-G needle;n = 3–10 mice/group). (C) Drop in body temperature at 24 hours after moderate CLP inTSLP receptor (Tslpr)+/+ mice (n = 19) andTslpr−/− mice (n = 17). Data were pooled from five independent experiments, each of which produced similar results. (D) Survival after moderate CLP inTslpr+/+ mice (n = 14) andTslpr−/− mice (n = 12). Data were pooled from the three independent experiments, each of which produced similar results. *P < 0.05 versusTslpr−/−. Data inA–C are presented as means (±SEM).
Figure 2.
Figure 2.
TSLPR deficiency enhances bacteria clearance after CLP. (A andB) Colony-forming units (CFUs) in the peritoneal lavage fluid (A) and blood (B) at 24 hours after moderate CLP inTslpr+/+ mice (n = 11–25) andTslpr−/− mice (n = 7–25). Data were pooled from six independent experiments.
Figure 3.
Figure 3.
TSLP–TSLPR interactions down-regulate inflammation after CLP. Neutrophil numbers in the peritoneal cavity (A), macrophage numbers in the peritoneal cavity (B), amounts of TNF, IL-6, IL-17, and keratinocyte chemoattractant (KC) in the plasma (C), and amounts of TNF, IL-6, IL-17, and KC in the peritoneal lavage fluids (D) at 24 hours after moderate CLP inTslpr+/+ mice (n = 12–25) andTslpr−/− mice (n = 12–25). ND, not detected. Data were pooled from six independent experiments. Data are presented as means (±SEM).
Figure 4.
Figure 4.
Myeloid cells with TSLPR deficiency exhibit increased production of proinflammatory cytokines after CLP. (A) TSLPR expression, as assessed by flow cytometry in bone marrow–derived neutrophils (Gr-1+; CD11b+) and peritoneal macrophages (F4/80+; CD11b+) from Cre−;Tslprfl/fl andLys-Cre+;Tslprfl/fl mice. Data are representative of three independent experiments. (B) mRNA expression forIl-6,Tnf,Il-1b,Il12p40, andIl-23p19 in peritoneal macrophages that were obtained from Cre−;Tslprfl/fl andLys-Cre+;Tslprfl/fl mice at 24 hours after CLP (n = 5). (C) Representative flow cytometry plots and frequencies for peritoneal neutrophils and macrophages obtained from Cre−;Tslprfl/fl andLys-Cre+;Tslprfl/fl mice at 24 hours after moderate CLP and reactivated by phorbol myristate acetate (PMA)/ionomycin for 4 hours in the presence of GolgiPlug. Cells were immunostained for IL-6 and surface granulocyte-differentiation antigen-1 (Gr-1) and CD11b for peritoneal neutrophils and F4/80 and CD11b for macrophages. Data are representative of three independent experiments. FSC, forward scatter; GAPDH, glyceraldehyde 3-phosphate dehydrogenase. Data are presented as means (±SEM).
Figure 5.
Figure 5.
TSLP reduces IL-6 production in human neutrophils. (A) TSLPR mRNA expression in human blood neutrophils (CD15+ cells) activated for 1 hour by either LPS (100 ng/ml) or GM-CSF (granulocyte/macrophage colony–stimulating factor; 100 ng/ml). (B–D) IL-6 mRNA expression (B), flow cytometry plots and frequencies (C), and IL-6 amounts in the supernatants (D) of activated human blood neutrophils that were pretreated with TSLP (100 ng/ml) and activated with LPS (100 ng/ml) for either 1 hour (B) or 4 hours (C andD). For the IL-6 intracellular staining (C), the cells were incubated in the presence of GolgiPlug for 4 hours and then immunostained for IL-6 and surface CD15. Data were pooled from four independent experiments. Data are presented as means (±SEM).
Figure 6.
Figure 6.
TSLP–TSLPR interactions in myeloid cells improve survival and reduce inflammation after CLP. (A) Survival after moderate CLP (50% ligation; single puncture with a 22-G needle) in Cre−;Tslprfl/fl (n = 17) andLys-Cre+;Tslprfl/fl mice (n = 12). Data were pooled from three independent experiments. (B) Plasma alanine aminotransferase (ALT) levels were assessed in naive Cre−;Tslprfl/fl (n = 3–7) andLys-Cre+;Tslprfl/fl (n = 3–9) mice and after moderate CLP. (C–F) CFUs in the peritoneal lavage fluid and blood (C), neutrophil numbers in the peritoneal cavity (D), macrophage numbers in the peritoneal cavity (E), and amounts of plasma TNF, IL-6, IL-17, and KC (F) at 24 hours after moderate CLP in Cre−;Tslprfl/fl (n = 7–17) andLys-Cre+;Tslprfl/fl mice (n = 13–24). Data were pooled from seven independent experiments. Data inB–F are presented as means (±SEM).
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References

    1. Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885–891. - PubMed
    1. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol. 2011;6:19–48. - PMC - PubMed
    1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–1310. - PubMed
    1. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–268. - PMC - PubMed
    1. Leonard WJ. TSLP: finally in the limelight. Nat Immunol. 2002;3:605–607. - PubMed

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