TSLP induces a proinflammatory phenotype in circulating innate cells and predicts prognosis in sepsis patients

Abstract

Thymic stromal lymphopoietin (TSLP) has been identified as a crucial inflammatory cytokine in immune homeostasis. Previous studies have reported conflicting effects of TSLP on sepsis in mice, and the effect of TSLP on sepsis in humans has not been investigated. In this study, we used the ELISA to measure serum levels of TSLP in patients with sepsis, and used flow cytometry and ELISA to evaluate the proinflammatory phenotype of circulating immune cells. In addition, we used quantitative RT‐PCR to examine the expression of proinflammatory cytokines [interleukin (IL)‐1β, IL‐6, tumor necrosis factor‐α, transferrin growth factor‐β, IL‐10, and matrix metalloproteinase] between patients with high and low levels of TSLP. Flow cytometry analysis was performed to evaluate the phagocytic and respiratory burst of circulating neutrophils. A significant increase in the production of proinflammatory cytokines by nonclassical monocytes and the number of interferon (IFN)‐γ+ CD4+ monocytes was observed in patients with high levels of TSLP. Furthermore, the number of IL‐10+ regulatory T cells was observed to be increased in patients with high levels of TSLP. We found that TSLP values greater than 350 pg·mL−1 were associated with a higher mortality rate and longer stays in intensive care (sensitivity of 89% and specificity of 79%). In patients with low levels of neutrophils, the area under curve was only 0.71 (based on the cutoff value in the diagnostic test evaluation; sensitivity of 62% and specificity of 68%). Our findings suggest that the serum levels of TSLP may be suitable as a biomarker for prediction of prognosis in a subgroup of patients with sepsis who are exhibiting hyperleukocytosis and a high neutrophil ratio.

Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression

“…Overall, they conclude that the upregulation of TSLP in sepsis aims to restore immune hemostasis by dampening inflammation (44). In contrast, Yu et al demonstrated a negative correlation between serum TSLP levels in patients with high ratio of neutrophils and increased mortality in a septic patient cohort (47). Moreover, they showed TSLP induces inflammation in neutrophils and T lymphocytes and certain monocyte subtypes (intermediate and non-classical) leading to increased production of e.g.…”

“…In trauma and sepsis, IL-10 is considered a key immunosuppressive cytokine and correlates with injury severity and outcomes (45) and is widely examined in sepsis and trauma studies. However, it has been demonstrated that all three cytokines also exert pro-inflammatory functions under certain conditions (46)(47)(48). This seems contradictory as they are considered key regulators of immunity.…”

“…First, a discrimination between the short and the long form should be conducted in future studies as their effects are considered to differ (139). Secondly, studies should differentiate between the severity of sepsis, as Piliponsky as well as Yu et al reported differences in the effect of TSLP regarding the severity of the disease (44,47). Thirdly, none of the studies so far address the release of TSLP by endothelial cells, which are considered the main producers (140).…”

“…TSLP has not been studied extensively in sepsis to date. Several studies provide conflicting results concerning the effect of TSLP in animal sepsis models or human studies ( 44 , 47 , 147 , 148 ). These findings are summarized in Table 3 and visualized in Figure 3 .…”

“…Moreover, they showed TSLP induces inflammation in neutrophils and T lymphocytes and certain monocyte subtypes (intermediate and non-classical) leading to increased production of e.g. IL-6, TNF-α and IFN-γ ( 47 ). They therefore conclude that TSLP has a pro-inflammatory effect on monocytes and lymphocytes but does not improve antibacterial clearance of neutrophils, as phagocytosis and respiratory burst were unchanged ( 47 ).…”