Cytokines and inflammation - GDR CNRS 3048  


  HEADProf. Jean-Marc CAVAILLON / jean-marc.cavaillon@pasteur.fr
  MEMBERSDr. Minou ADIB-CONQUY / Dr. Charlène BLANCHET / Dr. Noëlle DOYEN / Catherine FITTING / Fernando GUIMARAES / Dr. Oumaïma IBRAHIM-GRANET / Erin KHAN / Véronique MÉRIAUX / Dr. Marianna PARLATO / Dr. François PHILIPPART / Amélie SAVERS


  Annual Report

Interaction host cells - microorganisms

Innate immune Responses to Staphylococcus aureus

In response to heat-killed Staphylococcus aureus (HKSA), the mechanisms of activation leading to TNF production by murine mononuclear phagocytes (monocytes, peritoneal and alveolar macrophages) are specific for each population, involving different recognition processes and signaling pathways (Kapetanovic et al. Am J Physiol. Cell Physiol. 2011). NOD2 is not a crucial receptor to fight S. aureus-induced pneumonia, but the absence of NOD2 lead to a lesser inflammation, and is beneficial for the animal recovery (Kapetanovic et al. Microbes Infect. 2010; 12: 759).

Innate immune response to Biofilm-forming Pseudomonas aeruginosa

Biofilm-forming P. aeruginosa isolates induced higher production of TNF and IL-6 by human monocytes than their planktonic counterpart. P. aeruginosabiofilm lipopolysaccharide undergoes structural modifications contributing to an increased inflammatory response from human mononuclear phagocytes. (Ciornei et al. Innate Immunity 2010, 16: 288)

Aspergillus fumigatuspathophysiology

In vivo monitoring of fungal infection was performed using bioluminescentAspergillus fumigatus. An essential role for neutrophils as recruited phagocytes in the early steps of innate response to A. fumigatus was demonstrated (Ibrahim-Granet O et al. BMC Microbiol. 2010; 10: 105).The bioluminescent strain is also used to study the effectiveness of different antifungals and different combinations.

TLR9 intracellular trafficking and signalingduring the course of infection byL. major.

TLR9-deficient mice are more susceptible to Leishmania major than wild type mice, and murine dendritic cells (DCs) are activated by L. major, but DCs from TLR9-deficient mice are not (Abou Fakher et al. J. Immunol. 2009; 182: 1386). We investigate whethertranslocation of DNA into the endosomal compartment could be improved when DNA is associated with a cationic peptide. We also study the involvement of the asparagine endopeptidase, an enzymeknown to play a critical role in TLR9 processing and signaling in dendritic cells

Paradoxical effects of interleunkin-10 (IL-10)

We previously showed that the prevention of adherence of monocytes is a key parameter that prevents IL-10 to behave as an anti-inflammatory cytokine (Adib-Conquy et al. Int Immunol. 1999; 11: 689; Petit-Bertron et al. Cytokine. 2005; 29: 1-12). We have now developed a mouse model to study in vivothis paradoxical property of IL-10.

Resistance of alveolar macrophages to develop tolerance to TLR-agonists.

In contrast to other mouse mononuclear phagocytes, alveolar macrophages neither display endotoxin tolerance, nor cross-tolerance to other TLR agonists (Fitting et al. J. Infect. Dis. 2004, 189: 1295). The local influence of two cytokines known to prevent endotoxin tolerance, namely GM-CSF and gamma-interferon (IFNγ) contribute to prevent alveolar macrophages to be rendered tolerant. A cross-talk between B cells and NK cells is responsible for the presence of IFNγwithin the lungs.

The high resistance of mice to endotoxin renders them poorly suitable to mimic human sepsis.

We attempted to understand the reason forthe striking difference between human and murine sensitivity to the toxicity of endotoxin of Gram-negative bacteria (lipopolysaccharide, LPS). We pointed out a key factor or factors present in serum that account for that difference. (Warren et al. J. Infect. Dis. 2010, 210, 223).

Translational research

Markers of infection

Many inflammatory markers are found in plasma of sepsis and SIRS patients (Adib-Conquy & Cavaillon J-M. FEBS Lett. 2007, 581: 3723;Adib-Conquy et al. Shock 2007, 28: 406). As most probably a "magic marker" does not exist, a program has been set up to define the best combination of markers that would allow the early diagnosis of an infectious process among intensive care patients.

Alteration of immune status of monocytes in sepsis and SIRS patients

The concept of 'Compensatory anti-inflammatory response syndrome' (CARS) qualifies the consequences of the counter-regulatory mechanisms initiated to limit the overzealous inflammatory process in patients with infectious or non-infectious systemic inflammatory response syndrome (SIRS) (Adib-Conquy & Cavaillon. Thromb Haemost. 2009; 101: 36). We evaluated the role of the inflammatory status and apoptosis activation in the development of organ dysfunction after brain death (Adrie et al. Shock, 2010; 33: 353).Decreased expression of HLA-DR on monocytes is a hallmark of CARS. We studied this modification on monocyte subpopulations, and showed that the down-regulation of HLA-DR expression does not occur similarly among CD14HIGHCD16- and CD14LOWCD16+. HLA-DR on CD14HIGHand CD14LOWmonocytes of healthy donors is reduced following incubation with hydrocortisone, whereas IL-10 only acts on CD14HIGHcells (Kim et al.Crit. Care2010; 14: R61).

Keywords: Acute inflammation, Aspergillus fumigatus, Cytokines, Endotoxin, Innate immunity, Infection, Interleukin-6, Leishmania major, Macrophages, Nod-like receptors, Pathogen associated molecular patterns (PAMPs), Peptidoglycan, Sepsis, Staphylococcus aureus, Tolerance, Toll-like receptors, Tumor necrosis factor.

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From bacteria to infectious diseases. Interaction of microbial derived molecules with host's cells leads to the production of cytokines, a prerequisite for innate immunity. Overwhelming production is associated with severe inflammation while the concomitant anti-inflammatory response may be associated with increased susceptibility to nosocomial infection (Annane D, Bellissant E, Cavaillon J-M (2005)Septic Shock. The Lancet 365: 63-78).



  Publications

Kapetanovic R., Nahori M-A., Balloy V, Fitting C., Philpott D.J., Cavaillon J-M., Adib-Conquy M (2007) Contribution of phagocytosis and intracellular sensing for cytokine production by Staphylococcus aureus-activated macrophages. Infect. Immun. 75: 830-837

Brock M, Jouvion G, Droin-Bergère S, Dussurget O, Nicola MA, Ibrahim-Granet O. (2008)

Bioluminescent Aspergillus fumigatus, a new tool for drug efficiency testing and in vivo monitoring of invasive aspergillosis. Appl. Environ. Microbiol. 74: 7023-35

Abou Fakher FH, Rachinel N, Klimczak M, Louis J, Doyen N. (2009) TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions. J Immunol. 182:1386-96.

Kim O.Y., Monsel A., Bertrand M., Coriat P, Cavaillon J-M., Adib-Conquy M. (2010)

Differential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation. Crit. Care, 14(2):R61

Warren HS, Fitting C,Hoff E, Adib-Conquy M, Beasley-Topliffe L, Tesini B, Liang X, Valentine C, Hellman J, Hayden D, Cavaillon J-M. (2010) Resilience to bacterial infection: difference between species could be due to proteins in serum. J.Infect. Dis. 201: 223–32.

Key words

Acute inflammation, Aspergillus fumigatus, Cytokines, Endotoxin, Innate immunity, Infection, Interleukin-6, Leishmania major, Macrophages, Nod-like receptors, Pathogen associated molecular patterns (PAMPs), Peptidoglycan, Sepsis, Staphylococcus aureus, Tolerance, Toll-like receptors, Tumor necrosis factor.



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Activity Reports 2010 - Institut Pasteur
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