Effect of commercially available Plant Defence Stimulators on human innate immunity

National audiencePDS (Plant defence stimulators) constitute a recent alternative to pesticides used for crop protection. These compounds are of diverse nature, they all act by stimulating plant innate immune system and plants can better fight pathogens. There are many similarities in pathogen perception systems and cellular signalling in plants and animals. Many elicitors stimulate both human and plant innate immunity (Zipfel and Felix, 2005). Therefore, it is likely that human innate immunity could be modulated by PDS. The aim of this study is to evaluate pro/anti-inflammatory activity of five different commercially available PDS on human cell models. We studied the pro/anti-inflammatory effect of PDS on human peripheral blood mononuclear cells (PBMC). These cells are exposed during 20 h to various concentrations of PDS or their corresponding active molecules. Pro-inflammatory action is evaluated by measuring the quantity of the inflammatory cytokine IL-1β in the cells supernatants using ELISA test. To study anti-inflammatory effect, PBMC were treated with LPS to trigger a basal inflammatory response. We then checked if PDS delivered at the same time as LPS modified IL-1β production. In addition, in all the experiments, the viability is evaluated with a XTT test. PDS, which were however used at equal or lower concentrations than in the fields, show different profiles in terms of cytotoxicity and inflammatory modulation. Our results indicate that PDS can differently interact with human innate immunity

Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth

International audienceChemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4+ T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3−/− or Casp1−/− mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents