Abstract
Backgroundβ-glucans are fungal cell wall components that bind to the C-type lectin-like receptor dectin-1. Polymorphisms of dectin-1 gene are associated with susceptibility to invasive fungal infection and medically refractory ulcerative colitis. The purpose of this study has been addressing the response of human macrophages to β-glucans under different conditions mimicking the composition of the inflammatory milieu in view of the wide plasticity and large range of phenotypical changes showed by these cells, and the relevant role of dectin-1 in several pathophysiological conditions.Principal FindingsSerum-differentiated macrophages stimulated with β-glucans showed a low production of TNFα and IL-1β, a high production of IL-6 and IL-23, and a delayed induction of cyclooxygenase-2 and PGE2 biosynthesis that resembled the responses elicited by crystals and those produced when phagosomal degradation of the phagocytic cargo increases ligand access to intracellular pattern recognition receptors. Priming with a low concentration of LPS produced a rapid induction of cyclooxygenase-2 and a synergistic release of PGE2. When the differentiation of the macrophages was carried out in the presence of M-CSF, an increased expression of dectin-1 B isoform was observed. In addition, this treatment made the cells capable to release arachidonic acid in response to β-glucan.ConclusionsThese results indicate that the macrophage response to fungal β-glucans is strongly influenced by cytokines and microbial-derived factors that are usual components of the inflammatory milieu. These responses can be sorted into three main patterns i) an elementary response dependent on phagosomal processing of pathogen-associated molecular patterns and/or receptor-independent, direct membrane binding linked to the immunoreceptor tyrosine-based activation motif-bearing transmembrane adaptor DNAX-activating protein 12, ii) a response primed by TLR4-dependent signals, and iii) a response dependent on M-CSF and dectin-1 B isoform expression that mainly signals through the dectin-1 B/spleen tyrosine kinase/cytosolic phospholipase A2 route.
Highlights
Classical distinction between macrophage types includes the type M1 inflammatory macrophage and the M2 regulatory macrophage
These responses can be sorted into three main patterns i) an elementary response dependent on phagosomal processing of pathogen-associated molecular patterns and/or receptor-independent, direct membrane binding linked to the immunoreceptor tyrosine-based activation motif-bearing transmembrane adaptor DNAX-activating protein 12, ii) a response primed by TLR4-dependent signals, and iii) a response dependent on M-CSF and dectin-1 B isoform expression that mainly signals through the dectin-1 B/spleen tyrosine kinase/cytosolic phospholipase A2 route
The response of macrophages to b-glucans has mainly been studied in rodents and few reports have been conducted in human macrophages, even though dectin-1 plays a relevant role in human disease since polymorphisms of clec7a are associated with an increased risk of fungal infection [3] and medically refractory ulcerative colitis [4]
Summary
Classical distinction between macrophage types includes the type M1 inflammatory macrophage and the M2 regulatory macrophage. One of the most used macrophage stimuli are zymosan particles These contain b-glucans and a-mannans, and activate macrophages through different receptors, among which dectin-1 (encoded by the clec7a gene) is the most important receptor for b-glucans [2]. Transcription from human clec7a gives rise to the expression of several isoforms of the receptor [5], but a survey of dectin-1 expression along the differentiation of human macrophages has not been conducted yet This is of pathophysiological relevance since monocytes can display different responses to b-glucans [7,8]. Cooperation of dectin-1 and TLR2 is of particular relevance since the sole stimulation of mouse thioglycollate-elicited macrophages with purified b-glucans fails to induce cytokine production even though spleen tyrosine kinase (Syk) activation occurs, whereas combined stimulation of dectin-1 and TLR2 elicits a robust response in a MyD88 and Syk-dependent manner [16]. This mechanism mimics dectin-1 signaling that depends on its own ITAM
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