title: Aspergillus Cell Wall Chitin Induces Anti- and Proinflammatory Cytokines in Human PBMCs via the Fc-γ Receptor/Syk/PI3K Pathway.
abstract: Chitin is an important cell wall component of Aspergillus fumigatus conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from Aspergillus fumigatus Transcription and production of the proinflammatory cytokine interleukin-1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-γ-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not β-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen-associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin.
  
  
  
  Invasive aspergillosis and allergic aspergillosis are increasing health care problems. Patients get infected by inhalation of the airborne spores of Aspergillus fumigatus A profound knowledge of how Aspergillus and its cell wall components are recognized by the host cell and which type of immune response it induces is necessary to develop target-specific treatment options with less severe side effects than the treatment options to date. There is controversy in the literature about the receptor for chitin in human cells. We identified the Fc-γ receptor and Syk/PI3K pathway via which chitin can induce anti-inflammatory immune responses by inducing IL-1 receptor antagonist in the presence of human immunoglobulins but also proinflammatory responses in the presence of bacterial components. This explains why Aspergillus does not induce strong inflammation just by inhalation and rather fulfills an immune-dampening function. While in a lung coinfected with bacteria, Aspergillus augments immune responses by shifting toward a proinflammatory reaction.
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: K L
authors.initials: KL
authors.lastname: Becker
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Aimanianda
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Ammerdorffer
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Jacobs
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Gazendam
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: L A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Unité des Aspergillus, Institut Pasteur, Paris, France frank.vandeveerdonk@radboudumc.nl jean-paul.latge@pasteur.fr.
authors.forename: J P
authors.initials: JP
authors.lastname: Latgé
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands frank.vandeveerdonk@radboudumc.nl jean-paul.latge@pasteur.fr.
authors.forename: F L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002473:Cell Wall / Q000737:chemistry*; D002686:Chitin / Q000276:immunology* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008074:Lipoproteins / Q000494:pharmacology; D000069452:Pathogen-Associated Molecular Pattern Molecules / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D015398:Signal Transduction; D000072377:Syk Kinase / Q000276:immunology
chemical_list: D000119:Acetylmuramyl-Alanyl-Isoglutamine; D002686:Chitin; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008074:Lipoproteins; D000069452:Pathogen-Associated Molecular Pattern Molecules; D019869:Phosphatidylinositol 3-Kinases; D017452:Receptors, IgG; D000072377:Syk Kinase; C489017:FCGR1A protein, human; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine