PPARγ Controls Dectin-1 Expression Required for Host Antifungal Defense against Candida albicans

We recently showed that IL-13 or peroxisome proliferator activated receptor γ (PPARγ) ligands attenuate Candida albicans colonization of the gastrointestinal tract. Here, using a macrophage-specific Dectin-1 deficient mice model, we demonstrate that Dectin-1 is essential to control fungal gastrointestinal infection by PPARγ ligands. We also show that the phagocytosis of yeast and the release of reactive oxygen intermediates in response to Candida albicans challenge are impaired in macrophages from Dectin-1 deficient mice treated with PPARγ ligands or IL-13. Although the Mannose Receptor is not sufficient to trigger antifungal functions during the alternative activation of macrophages, our data establish the involvement of the Mannose Receptor in the initial recognition of non-opsonized Candida albicans by macrophages. We also demonstrate for the first time that the modulation of Dectin-1 expression by IL-13 involves the PPARγ signaling pathway. These findings are consistent with a crucial role for PPARγ in the alternative activation of macrophages by Th2 cytokines. Altogether these data suggest that PPARγ ligands may be of therapeutic value in esophageal and gastrointestinal candidiasis in patients severely immunocompromised or with metabolic diseases in whom the prevalence of candidiasis is considerable

Community Autonomy from Past to Present: Partnerships between the State and Philanthropic Foundation in Quebec as a reform of public action

International audienc

Artesunate and severe malaria in paediatrics

peer reviewedMalaria is a life-threatening infection which affects especially non-immune subjects including children under the age of 5. Imported malaria is a rare disease in Europe but, with the increasing number of travelers and people who are visiting friends or relatives, it is important not to neglect it. Severe malaria leads to many pediatric deaths in countries with limited resources. The treatment of choice is a parenteral antimalarial. For a long time, only quinine was used in that case. Based on strong studies conducted in Asia and Africa, WHO (World Health Organization) has recommended the use of artesunate as a first-line treatment for severe malaria in adults and children since 2010.The use of artesunate has shown a reduction in mortality rate in severe malaria. In Europe, there still are several barriers to the implementation of these recommendations, especially in terms of availability and cost. In pediatrics departments and adults, artesunate is the first-line treatment in severe malaria, although close monitoring is essential, especially at the hematological side, monitoring the development of delayed post-artesunate haemolytic anemia (PADH), a known side effect

Community Autonomy from Past to Present: Partnerships between the State and Philanthropic Foundation in Quebec as a reform of public action

International audienc

Splénomégalie palustre hyperimmune et drépanocytose. A propos d'un cas

peer reviewe

Gonoccocal ophtlamia neonatorum: still present

peer reviewedL’ophtalmie néonatale n’appartient pas qu’au passé, l’incidence d’infections à Neisseria Gonorrhaea étant en augmentation en Belgique. Différentes prophylaxies sont proposées (nitrate d’argent, povidone iodine, tétracycline, érythromycine, acide fusidique), avec leurs avantages et inconvénients respectifs. Aucun consensus clair n’est établi quant à la solution la plus efficace, certains remettant en doute leur utilisation dans les pays développés

PPARγ inhibition in M2 polarized macrophages abolishes the increase of Dectin-1.

<p>(A) The protein level of Dectin-1 on peritoneal macrophages was measured by flow cytometry after treatment with IL-13 (50 ng/mL) or rosiglitazone (RZ) (5 µM) in the presence of the PPARγ antagonists (GW9662 (5 µM) and T007 (2 µM)). Data are the means±SE of three separate experiments. (B) Dectin-1 mRNA level of peritoneal macrophages was quantified by quantitative real-time RT-PCR after treatment with IL-13 (50 ng/mL) or rosiglitazone (RZ) (5 µM) in the presence of the PPARγ antagonist (GW9662 (5 µM)). Data are the means±SE of three separate experiments. ** (p<0.01) and * (p<0.05) indicates a significant difference compared with the untreated macrophages. (C) The surface protein level of Dectin-1 on peritoneal macrophages transfected with siRNA targeting PPARγ (PPARγ siRNA) or control siRNA (control siRNA) and stimulated by IL-13. Representative Dectin-1 FACS profiles of untreated (unfilled histograms) and treated (filled histograms) macrophages were obtained by flow cytometry. The changes in Dectin-1 receptor levels were normalized to the untreated macrophages transfected with the siRNA control. Data are the means±SE of three separate experiments. ** (p<0.01) and * (p<0.05) indicates significant difference compared with the untreated macrophages transfected with the siRNA control.</p

Dectin-1 and the Mannose Receptor are implicated in antifungal functions of macrophages treated with IL-13 or PPARγ ligand.

<p>Peritoneal macrophages were cultured with IL-13 (50 ng/mL) (A and B) or rosiglitazone (5 µM) (C and D). Mannan (mann) and/or soluble β-glucan (laminarin, lam) solutions were incubated at 4°C for 20 min until the phagocytosis and respiratory burst experiments. (A and C) The phagocytosis of non-opsonized <i>C.albicans</i> (ratio 1∶6) by macrophages was measured at 37°C after exposure to FITC-labeled <i>C.albicans</i> for 60 min. The amount of fluorescence was determined using a FACS based approach. The distinction between internalized yeast cells and those attached to macrophage surface was done <i>via</i> quenching the FITC-fluorescence with trypan blue. Data are expressed as percentage relative to untreated control macrophages and are means±SE of three separate experiments. (B and D) Non-opsonized <i>C.albicans</i>-induced respiratory burst of macrophages (ratio 1∶3) was measured by chimiluminescence. Total chemiluminescence emission (area under the curve expressed in counts x seconds) was observed continuously for 60 min in the presence or absence of non-opsonized <i>C. albicans</i>. The data are the means±SE of three separate experiments. ** (p<0.01) and * (p<0.05) indicates a significant difference compared with the untreated macrophages. ## (p<0.01) and # (p<0.05) indicates a significant difference compared with the treated control macrophages.</p

Dectin-1-knockout mice are more susceptible than Dectin-1-wildtype mice to <i>C. albicans</i> gastrointestinal infection.

<p>(A and B) Quantification of <i>C. albicans</i> fungal burden in the gastrointestinal tract (stomach and cecum) of Dectin-1-control mice Cre 0 (filled circles) and Dectin-1-knockout mice Cre Tg (open circles) at 5 day after oral infection with 5.10⁶ CFU (A, n = 6) or with 5.10⁷ CFU (B, n = 4) in standard conditions or after treatment with rosiglitazone (RZ) (2.8 µg/g of mouse). Each symbol represents an individual mouse. § (p<0.05) indicates a significant difference between group of mice. (C) Phagocytosis and ROS production were measured on peritoneal macrophages from Dectin-1 knockout (Cre Tg) mice at 5 day after oral infection with 5.10⁶ CFU in standard conditions or after treatment with rosiglitazone (RZ). The phagocytosis of non-opsonized <i>C.albicans</i> by macrophages was measured at 37°C after exposure to FITC-labeled <i>C.albicans</i> for 60 min (ratio 1∶6). The amount of fluorescence was determined using a FACS based approach. The distinction between internalized yeast cells and those attached to macrophage surface was done <i>via</i> quenching the FITC-fluorescence with trypan blue. Data are expressed as the percentage relative to untreated Dectin-1 control (Cre 0) macrophages and are the means±SE (n = 6). The respiratory burst of macrophages induced by non-opsonized zymosan (ZNO) (2 µg/mL) was measured by chimiluminescence. Total chemiluminescence emission (area under the curve expressed in counts x seconds) was observed continuously for 60 min. Data are the means±SE (n = 6). ** (p<0.01) indicates a significant difference compared with the Cre 0 untreated macrophages. § (p<0.05) indicates a significant difference between Cre 0 and Cre Tg. (D) The MR surface protein level was measured by flow cytometry on peritoneal macrophages from Dectin-1 control (Cre 0) or Dectin-1 knockout (Cre Tg) mice at day 5 after oral infection with 5.10⁷ CFU in standard conditions or after treatment with rosiglitazone (RZ). Data are the means±SE (n = 4). ** (p<0.01) indicates a significant difference compared with the Cre 0 control. § (p<0.05) indicates a significant difference between Cre 0 and Cre Tg.</p