Zoledronate rescues immunosuppressed monocytes in sepsis patients.
Loïc RaffrayRoss J BurtonSarah E BakerMatt P MorganMatthias EberlPublished in: Immunology (2019)
Severe sepsis is often accompanied by a transient immune paralysis, which is associated with enhanced susceptibility to secondary infections and poor clinical outcomes. The functional impairment of antigen-presenting cells is considered to be a major hallmark of this septic immunosuppression, with reduced HLA-DR expression on circulating monocytes serving as predictor of mortality. Unconventional lymphocytes like γδ T-cells have the potential to restore immune defects in a variety of pathologies including cancer, but their use to rescue sepsis-induced immunosuppression has not been investigated. Our own previous work showed that Vγ9/Vδ2+ γδ T-cells are potent activators of monocytes from healthy volunteers in vitro, and in individuals with osteoporosis after first-time administration of the anti-bone resorption drug zoledronate in vivo. We show here that zoledronate readily induces upregulation of HLA-DR, CD40 and CD64 on monocytes from both healthy controls and sepsis patients, which could be abrogated by neutralising the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α in the cultures. In healthy controls, the upregulation of HLA-DR on monocytes was proportional to the baseline percentage of Vγ9/Vδ2 T-cells in the peripheral blood mononuclear cell population. Of note, a proportion of sepsis patients studied here did not show a demonstrable response to zoledronate, predominantly patients with microbiologically confirmed bloodstream infections, compared with sepsis patients with more localised infections marked by negative blood cultures. Taken together, our results suggest that zoledronate can, at least in some individuals, rescue immunosuppressed monocytes during acute sepsis and thus may help improve clinical outcomes during severe infection.
Keyphrases
- peripheral blood
- acute kidney injury
- end stage renal disease
- dendritic cells
- intensive care unit
- septic shock
- newly diagnosed
- ejection fraction
- poor prognosis
- chronic kidney disease
- rheumatoid arthritis
- immune response
- prognostic factors
- peritoneal dialysis
- mass spectrometry
- squamous cell carcinoma
- emergency department
- signaling pathway
- long non coding rna
- type diabetes
- cardiovascular disease
- cell proliferation
- drug induced
- oxidative stress
- patient reported outcomes
- cell death
- endoplasmic reticulum stress
- editorial comment
- single cell
- human health
- liver failure
- cell therapy
- climate change
- acute respiratory distress syndrome
- extracorporeal membrane oxygenation
- high speed
- diabetic rats