Fungal Recognition Enhances Mannose Receptor Shedding through Dectin-1 Engagement

Abstract

The mannose receptor (MR) is an endocytic type I membrane molecule with a broad ligand specificity that is involved in both hemostasis and pathogen recognition. Membrane-anchored MR is cleaved by a metalloproteinase into functional soluble MR (sMR) composed of the extracellular domains of intact MR. Although sMR production was initially considered a constitutive process, enhanced MR shedding has been observed in response to the fungal pathogen Pneumocystis carinii. In this work, we have investigated the mechanism mediating enhanced MR shedding in response to fungi. We show that other fungal species, including Candida albicans and Aspergillus fumigatus, together with zymosan, a preparation of the cell wall of Saccharomyces cerevisiae, mimic the effect of P. carinii on sMR production and that this effect takes place mainly through β-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate β-glucan requires expression of dectin-1. Our data, obtained using specific inhibitors, are consistent with the canonical Syk-mediated pathway triggered by dectin-1 being mainly responsible for inducing MR shedding, with Raf-1 being partially involved. As in the case of steady-state conditions, MR shedding in response to C. albicans and β-glucan particles requires metalloprotease activity. The induction of MR shedding by dectin-1 has clear implications for the role of MR in fungal recognition, as sMR was previously shown to retain the ability to bind fungal pathogens and can interact with numerous host molecules, including lysosomal hydrolases. Thus, MR cleavage could also impact on the magnitude of inflammation during fungal infection.

Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders

“…1). 91 Although these findings seem promising for the qualification of sMMR as a fungal biomarker, a recent small study in the ICU found sMMR concentrations to be elevated in patients with non-infectious SIRS (trauma and intracranial hemorrhage) and as well as bacterial sepsis. 49 …”

A Maize Cystatin Suppresses Host Immunity by Inhibiting Apoplastic Cysteine Proteases

“…Another possible mechanism of protease-mediated signaling is the proteolytic shedding of extracellular receptor domains by matrix metalloproteases. In animal systems, this mechanism has been identified as a common principle in various diseases, including cancer (Peschon et al, 1998;Choi et al, 2010), and also during invasion of fungal pathogens (Gazi et al, 2011). As another example, subtilisin-like proteases, termed phytaspases (plant Asp-specific protease), were identified in rice (Oryza sativa) and tobacco.…”

Sinusoidal Immunity: Macrophages at the Lymphohematopoietic Interface

“…Mutational analysis of the CR-Fc established the specificity of targeting. Soluble MR, shed by TACE-like metalloproteinases from the surface of APC (e.g., after phagocytic stimulation) (Gazi et al 2011), could similarly interact with MMM subpopulations and modulate B-cell responses.…”