Aspergillus Cell Wall Chitin Induces Anti- and Proinflammatory Cytokines in Human PBMCs via the Fc-γ Receptor/Syk/PI3K Pathway.

K L Becker,A Ammerdorffer,R P Gazendam,M G Netea,C W Jacobs,X Wang,J P Latgé,V Aimanianda,L A B Joosten,F L Van De Veerdonk,M S Gresnigt

doi:10.1128/mbio.01823-15

Abstract

ABSTRACTChitin 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.

Highlights

Conidia of the opportunistic fungus Aspergillus fumigatus are responsible for allergic syndromes, especially allergic bronchopulmonary aspergillosis
We aimed to elucidate the immunological properties of chitin isolated from the A. fumigatus cell wall and its receptor in human peripheral blood mononuclear cells (PBMCs) and the mechanism and circumstances under which chitin can switch between anti-inflammatory immune responses toward proinflammatory responses
No pattern recognition receptor or signaling pathway activated by chitin has been identified in human immune cells to date, and immunostimulatory capacities range from absence of effects to anti-inflammatory and even proinflammatory properties [16]

Summary

Introduction

Conidia of the opportunistic fungus Aspergillus fumigatus are responsible for allergic syndromes, especially allergic bronchopulmonary aspergillosis. Chitin was described to have proinflammatory properties by inducing IL-17 via the Toll-like receptor 2 (TLR2) pathway [10] in murine cells, and a recent study suggested recognition of chitin via the mannose receptor (MR) on the surface of the phagocytes and by the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 receptors in the cytoplasm, leading to the induction of the antiinflammatory cytokine IL-10 in mouse macrophages [11]. We aimed to elucidate the immunological properties of chitin isolated from the A. fumigatus cell wall and its receptor in human peripheral blood mononuclear cells (PBMCs) and the mechanism and circumstances under which chitin can switch between anti-inflammatory immune responses toward proinflammatory responses

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