The mannose receptor Martinez-Pomares, Luisa
Journal of leukocyte biology
92, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The MR is a highly effective endocytic receptor with a broad binding specificity encompassing ligands of microbial and endogenous origin and a poorly characterized ability to modulate cellular ...activation. This review provides an update of the latest developments in the field. It discusses how MR biology might be affected by glycosylation and proteolytic processing, MR involvement in antigen delivery, and the potential contribution of MR to T cell differentiation and cellular activation. Further understanding of these areas will, no doubt, inform the design of novel, therapeutic tools for improved vaccination, control of inflammation, and tumor chemotherapy, which will benefit from exploiting MR-efficient internalization properties and unique pattern of expression.
CD169+ macrophages have fascinated immunologists because of their unique distribution in secondary lymphoid organs, redistribution upon immune activation and, lately, because of their contribution to ...antigen handling. Their association with B cell follicles prompted early studies on their involvement in B cell activation, and recent work has unveiled an unexpected role in facilitating activation of other lymphocyte subsets, such as invariant natural killer T (iNKT) cells. New data also argue that CD169+ macrophages activate CD8 T cells in response to dead cell-associated antigens in lymph nodes and by transferring antigen to dendritic cells (DCs) in the spleen. Understanding the role of CD169+ macrophages in the activation of acquired immunity could benefit the design of vaccination strategies, for example those aimed at eliciting cytotoxic T cells.
Hemocyanins are used as immunomodulators in clinical applications because they induce a strong Th1‐biased cell‐mediated immunity, which has beneficial effects. They are multiligand glycosylated ...molecules with abundant and complex mannose‐rich structures. It remains unclear whether these structures influence hemocyanin‐induced immunostimulatory processes in human APCs. We have previously shown that hemocyanin glycans from Concholepas concholepas (CCH), Fissurella latimarginata (FLH), and Megathura crenulata (KLH), participate in their immune recognition and immunogenicity in mice, interacting with murine C‐type lectin receptors (CLRs). Here, we studied the interactions of these hemocyanins with two major mannose‐binding CLRs on monocyte‐derived human DCs: MR (mannose receptor) and DC‐SIGN (DC‐specific ICAM‐3–grabbing nonintegrin). Diverse analyses showed that hemocyanins are internalized by a mannose‐sensitive mechanism. This process was calcium dependent. Moreover, hemocyanins colocalized with MR and DC‐SIGN, and were partly internalized through clathrin‐mediated endocytosis. The hemocyanin‐mediated proinflammatory cytokine response was impaired when using deglycosylated FLH and KLH compared to CCH. We further showed that hemocyanins bind to human MR and DC‐SIGN in a carbohydrate‐dependent manner with affinity constants in the physiological concentration range. Overall, we showed that these three clinically valuable hemocyanins interact with human mannose‐sensitive CLRs, initiating an immune response and promoting a Th1 cell‐driving potential.
Mollusk hemocyanin bind with high affinity constants to human MR and DC‐SIGN leading to their endocytosis. The CLR‐mediated endocytosis is occurring in human monocyte derived cells and is dependent on hemocyanin glycosylation. This process leads to proinflammatory cytokine secretion by DCs, explaining partially their immunomodulator effect.
Abstract Mannose receptor (MR) is a C-type lectin primarily expressed by macrophages and dendritic cells. Its three distinct extracellular binding sites recognise a wide range of both endogenous and ...exogenous ligands, therefore MR has been implicated in both homeostatic processes and pathogen recognition. However, the function of MR in host defence is not yet clearly understood as MR-deficient animals do not display enhanced susceptibility to pathogens bearing MR ligands. This scenario is even more complex when considering the role of MR in innate immune activation as, even though no intracellular signalling motif has been identified at its cytoplasmic tail, MR has been shown to be essential for cytokine production, both pro-inflammatory and anti-inflammatory. Furthermore, MR might interact with other canonical pattern recognition receptors in order to mediate intracellular signalling. In this review, we have summarised recent observations relating to MR function in immune responses and focused on its participation in phagocytosis, antigen processing and presentation, cell migration and intracellular signalling.
Ag delivery to specific APCs is an attractive approach in developing strategies for vaccination. CD169+ macrophages in the marginal zone of the spleen represent a suitable target for delivery of Ag ...because of their strategic location, which is optimal for the capture of blood‐borne Ag and their close proximity to B cells and T cells in the white pulp. Here we show that Ag targeting to CD169+ macrophages in mice resulted in strong, isotype‐switched, high‐affinity Ab production and the preferential induction and long‐term persistence of Ag‐specific GC B cells and follicular Th cells. In agreement with these observations, CD169+ macrophages retained intact Ag, induced cognate activation of B cells, and increased expression of costimulatory molecules upon activation. In addition, macrophages were required for the production of cytokines that promote B‐cell responses. Our results identify CD169+ macrophages as promoters of high‐affinity humoral immune responses and emphasize the value of CD169 as target for Ag delivery to improve vaccine responses.
Physiological roles of macrophages Gordon, Siamon; Martinez-Pomares, Luisa
Pflügers Archiv,
04/2017, Letnik:
469, Številka:
3-4
Journal Article, Book Review
Recenzirano
Odprti dostop
Macrophages are present in mammals from midgestation, contributing to physiologic homeostasis throughout life. Macrophages arise from yolk sac and foetal liver progenitors during embryonic ...development in the mouse and persist in different organs as heterogeneous, self-renewing tissue-resident populations. Bone marrow-derived blood monocytes are recruited after birth to replenish tissue-resident populations and to meet further demands during inflammation, infection and metabolic perturbations. Macrophages of mixed origin and different locations vary in replication and turnover, but are all active in mRNA and protein synthesis, fulfilling organ-specific and systemic trophic functions, in addition to host defence. In this review, we emphasise selected properties and non-immune functions of tissue macrophages which contribute to physiologic homeostasis.
Macrophages are important orchestrators of inflammation during bacterial infection, acting as both effector cells and regulators of neutrophil recruitment and life span. Differently activated ...macrophage populations with distinct inflammatory and microbicidal potentials have been described. Our previous work unveiled a positive and a negative correlation between levels of gamma interferon (IFN-γ) and interleukin-17A (IL-17A), respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with
This study sought to define key parameters in human antibacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimize tissue damage while maximizing bacterial clearance. Toward this aim, neutrophils were incorporated into cultures of macrophages treated with IFN-γ or IL-17A and infected with
The intent of this design was to model (i) initiation of inflammation by infected macrophages and (ii) delayed arrival of neutrophils and their exposure to macrophage-derived cytokines. Under these conditions, IFN-γ decreased bacterial killing and promoted the production of monocyte chemoattractant protein 1 (MCP-1). In contrast, IL-17A promoted bacterial killing but did not affect MCP-1 production. The level of secretion of the pyrogen IL-1β was significantly lower in the presence of IFN-γ than in the presence of IL-17A and correlated with levels of the
transcript in infected macrophages. These findings support the validity of this model to investigate human antibacterial immunity. Based on these observations, the protective and damaging roles of IFN-γ and IL-17A, respectively, during
infection could be caused by their contrasting effects on IL-1β and MCP-1 production.
Mollusk hemocyanins have biomedical uses as carriers/adjuvants and nonspecific immunostimulants with beneficial clinical outcomes by triggering the production of proinflammatory cytokines in ...antigen-presenting cells (APCs) and driving immune responses toward type 1 T helper (Th1) polarization. Significant structural features of hemocyanins as a model antigen are their glycosylation patterns. Indeed, hemocyanins have a multivalent nature as highly mannosylated antigens. We have previously shown that hemocyanins are internalized by APCs through receptor-mediated endocytosis with proteins that contain C-type lectin domains, such as mannose receptor (MR). However, the contribution of other innate immune receptors to the proinflammatory signaling pathway triggered by hemocyanins is unknown. Thus, we studied the roles of Dectin-1, Dectin-2, and Toll-like receptor 4 (TLR4) in the hemocyanin activation of murine APCs, both in dendritic cells (DCs) and macrophages, using hemocyanins from
KLH),
(CCH) and
(FLH). The results showed that these hemocyanins bound to chimeric Dectin-1 and Dectin-2 receptors
; which significantly decreased when the glycoproteins were deglycosylated. However, hemocyanin-induced proinflammatory effects in APCs from Dectin-1 knock-out (KO) and Dectin-2 KO mice were independent of both receptors. Moreover, when wild-type APCs were cultured in the presence of hemocyanins, phosphorylation of Syk kinase was not detected. We further showed that KLH and FLH induced ERK1/2 phosphorylation, a key event involved in the TLR signaling pathway. We confirmed a glycan-dependent binding of hemocyanins to chimeric TLR4
. Moreover, DCs from mice deficient for MyD88-adapter-like (Mal), a downstream adapter molecule of TLR4, were partially activated by FLH, suggesting a role of the TLR pathway in hemocyanin recognition to activate APCs. The participation of TLR4 was confirmed through a decrease in IL-12p40 and IL-6 secretion induced by FLH when a TLR4 blocking antibody was used; a reduction was also observed in DCs from C3H/HeJ mice, a mouse strain with a nonfunctional mutation for this receptor. Moreover, IL-6 secretion induced by FLH was abolished in macrophages deficient for TLR4. Our data showed the involvement of TLR4 in the hemocyanin-mediated proinflammatory response in APCs, which could cooperate with MR in innate immune recognition of these glycoproteins.
Pseudomonas aeruginosa is an opportunistic pathogen that can cause severe infections at compromised epithelial surfaces, such those found in burns, wounds, and in lungs damaged by mechanical ...ventilation or recurrent infections, particularly in cystic fibrosis (CF) patients. CF patients have been proposed to have a Th2 and Th17-biased immune response suggesting that the lack of Th1 and/or over exuberant Th17 responses could contribute to the establishment of chronic P. aeruginosa infection and deterioration of lung function. Accordingly, we have observed that interferon (IFN)-γ production by peripheral blood mononuclear cells from CF patients positively correlated with lung function, particularly in patients chronically infected with P. aeruginosa. In contrast, IL-17A levels tended to correlate negatively with lung function with this trend becoming significant in patients chronically infected with P. aeruginosa. These results are in agreement with IFN-γ and IL-17A playing protective and detrimental roles, respectively, in CF. In order to explore the protective effect of IFN-γ in CF, the effect of IFN-γ alone or in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), on the ability of human macrophages to control P. aeruginosa growth, resist the cytotoxicity induced by this bacterium or promote inflammation was investigated. Treatment of macrophages with IFN-γ, in the presence and absence of GM-CSF, failed to alter bacterial growth or macrophage survival upon P. aeruginosa infection, but changed the inflammatory potential of macrophages. IFN-γ caused up-regulation of monocyte chemoattractant protein-1 (MCP-1) and TNF-α and down-regulation of IL-10 expression by infected macrophages. GM-CSF in combination with IFN-γ promoted IL-6 production and further reduction of IL-10 synthesis. Comparison of TNF-α vs. IL-10 and IL-6 vs. IL-10 ratios revealed the following hierarchy in regard to the pro-inflammatory potential of human macrophages infected with P. aeruginosa: untreated < treated with GM-CSF < treated with IFN-γ < treated with GM-CSF and IFN-γ.
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