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Complement receptor type 3 (CR3)- and Fc receptor (FcR)-mediated metalloproteinase-9 (MMP-9) secretion and their intracellular signalling of bovine neutrophils were evaluated. Relative density of MMP-9 secreted by neutrophils stimulated with opsonized zymosan (OPZ, stimulant for CR3) was significantly (p < 0.05) increased when the OPZ concentration was increased from 0 to 0.4 mg/ml. Similar results were obtained for neutrophils stimulated with heat-aggregated IgG (Agg-IgG, stimulant for Fc receptor) at concentrations from 0 to 0.40 mg/ml. Preincubation of neutrophils with 1-30 nmol/L wortmannin (phosphoinositide 3-kinase inhibitor) resulted in inhibition of MMP-9 secretion induced by stimulation with OPZ and Agg-IgG in a concentration-dependent manner, 30 nmol/L wortmannin causing complete inhibition. Similarly, preincubation of neutrophils with 0-100 μmol/L genistein (tyrosine kinase inhibitor) also resulted in inhibition of OPZ- and Agg-IgG-induced MMP-9 secretion in a concentration-dependent manner, with 100 μmol/L genistein causing complete inhibition. Significant (p < 0.05) positive correlations were found between MMP-9 and luminal-dependent chemiluminescent response (LDCL) in the case of stimulation with OPZ (r = 0.754) and in the case of stimulation with Agg-IgG (r = 0.728). Our findings suggested that CR3 and FcR play a critical role in production of MMP-9 and may be regulated by intracellular signal transduction, including that by phosphoinositide 3-kinase (PI3K) and tyrosine kinase (TK).

Neuronal elimination in the developing CNS is accomplished by an orderly type of cellular suicide called programmed cell death. The principal non-neuronal cells implicated in regulating programmed cell death and subsequent phagocytosis of dying neurons are the brain’s macrophage population, the microglia. Little is known about the signaling between microglia and neurons during programmed cell death. However, macrophages in non-neural tissues express receptors for immunoglobulin (IgG) and complement, and these molecules help regulate phagocytosis of dying cells and foreign organisms. Since many of the neurons generated early in CNS development are transient cell types that are immunoreactive for IgG [Upender et al.: J Comp Neurol 1997; 384:271–282], we hypothesized that IgG might alter the phagocytic properties of microglia within the developing nervous system and potentiate engulfment of dying cells. To begin to address this hypothesis, we first asked whether cortical neurons immunoreactive for IgG or calbindin-D28k exhibit morphological evidence of programmed cell death in the cerebral cortex of neonatal rat pups. Secondly, we quantified the incidence of contacts made by microglia on IgG- vs. calbindin-immunoreactive neurons. Thirdly, perturbation experiments were performed to elevate intracortical levels of IgG and the incidence of microglia:neuron contacts were determined. We found that although the nuclei of some IgG-immunoreactive neurons exhibited condensation and fragmentation characteristic of programmed cell death, we did not observe pyknotic calbindin-immunoreactive neurons. IgG-immunoreactive neurons were also more likely to be contacted by microglia than calbindin-immunoreactive neurons. Elevating intracortical levels of IgG experimentally led to a dramatic increase in the expression of microglia complement receptors throughout the cerebral cortex. Taken together, these results suggest that IgG normally present within neuronal subsets in the developing cerebral cortex could serve to locally regulate the expression of complement receptors on microglia.

Phagocytosis is a specialized process that enables cellular ingestion and clearance of microbes, dead cells and tissue debris that are too large for other endocytic routes. As such, it is an essential component of tissue homeostasis and the innate immune response, and also provides a link to the adaptive immune response. However, ingestion of large particulate materials represents a monumental task for phagocytic cells. It requires profound reorganization of the cell morphology around the target in a controlled manner, which is limited by biophysical constraints. Experimental and theoretical studies have identified critical aspects associated with the interconnected biophysical properties of the receptors, the membrane, and the actin cytoskeleton that can determine the success of large particle internalization. In this review, we will discuss the major physical constraints involved in the formation of a phagosome. Focusing on two of the most-studied types of phagocytic receptors, the Fcγ receptors and the complement receptor 3 (αMβ2 integrin), we will describe the complex molecular mechanisms employed by phagocytes to overcome these physical constraints.

•β-glucans are biological response modifiers with rich sources and diverse structures.•Extensive studies of β-glucan have been carried out to demonstrate its adjuvant activity on anti-infection vaccination and anti-tumor therapy.•The immunoadjuvant effects of β-glucans are mainly depending on the recognition of specific receptors such as dectin-1 and CR3. β-glucans, a group of polysaccharides exist in many organism species such as mushrooms, yeasts, oats, barley, seaweed, but not mammalians, have a variety of biological activities and applications in drugs and other healthcare products. In recent years, β-glucans have been studied as adjuvants in anti-infection vaccines as well as immunomodulators in anti-cancer immunotherapy. β-glucans can regulate immune responses when administered alone and can connect innate and adaptive immunity to improve immunogenicity of vaccines. When β-glucans act as immunostimulants or adjuvants, a set of receptors have been revealed to recognize β-glucans, including dectin-1, complement receptor 3 (CR3), CD5, lactosylceramide, and so on. Therefore, this review is mainly focused on the application of β-glucans as immune adjuvants, the receptors of β-glucans, as well as their structure and activity relationship which will benefit future research of β-glucans.

Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases. FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.

Importantly, our study highlights an unusual target on DCs—the α chain of complement receptor 4 (CR4) (CD11c)—for therapeutic interventions in HIV-1 treatment. Targeting CD11c on DCs mediated a potent antiviral immune response via clustering of CR4 and CCR5 and subsequent opening of an antiviral recognition pathway in DCs via MAVS. Complement-opsonized HIV-1 triggers efficient antiviral type I interferon (IFN) responses in dendritic cells (DCs), which play an important role in protective responses at the earliest stages in retroviral infection. In contrast, HIV-1 suppresses or escapes sensing by STING- and MAVS-associated sensors. Here, we identified a complement receptor-mediated sensing pathway, where DCs are activated in CCR5/RLR (RIG-I/MDA5)/MAVS/TBK1-dependent fashion. Increased fusion of complement-opsonized HIV-1 via complement receptor 4 and CCR5 leads to increased incoming HIV-1 RNA in the cytoplasm, sensed by a nonredundant cooperative effect of RIG-I and MDA5. Moreover, complement-opsonized HIV-1 down-modulated the MAVS-suppressive Raf-1/PLK1 pathway, thereby opening the antiviral recognition pathway via MAVS. This in turn was followed by MAVS aggregation and subsequent TBK1/IRF3/NF-κB activation in DCs exposed to complement- but not non-opsonized HIV-1. Our data strongly suggest that complement is important in the induction of efficient antiviral immune responses by preventing HIV-1 suppressive mechanisms as well as inducing specific cytosolic sensors. IMPORTANCE Importantly, our study highlights an unusual target on DCs—the α chain of complement receptor 4 (CR4) (CD11c)—for therapeutic interventions in HIV-1 treatment. Targeting CD11c on DCs mediated a potent antiviral immune response via clustering of CR4 and CCR5 and subsequent opening of an antiviral recognition pathway in DCs via MAVS. This novel finding might provide novel tools for specifically boosting endogenous antiviral immunity via CR4, abundantly expressed on multiple DC subsets.

The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3/3a (C3/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.

In addition to alpha1,3 glucan, mannan and mannan-linked proteins are expressed in the outer layer of Paracoccidioides brasiliensis yeasts. The recognition of mannosyl residues by multiple pathogen recognition receptors, such as the mannose receptor (MR), complement receptor 3 (CR3) and toll-like receptor 4 (TLR4) on macrophage membranes can influence macrophage activation and the mechanisms of innate immunity against fungal pathogens. The aim of this study was to clarify the role of these receptors in the interaction between P. brasiliensis and macrophages from resistant (A/J) and susceptible (B10.A) mice. Therefore, the phagocytic, fungicidal and secretory abilities of macrophages were evaluated in the presence of mannan and antibodies against MR, CR3 and TLR4. We verified that mannan increased and anti-MR antibody decreased the killing ability and nitric oxide production of macrophages. The specific blockade of MR, CR3 and TLR4 by monoclonal antibodies impaired fungal recognition and modulated the production of cytokines. Mannan or P. brasiliensis induced decreased expression of MR and TLR2 on A/J macrophages, whereas CR3, TLR4 and TLR2 were reduced on B10.A cells. Importantly, both mannan and P. brasiliensis induced the production of IL-12 by B10.A macrophages, whereas TGF-β, TNF-α and IL-6 were produced by A/J cells. In addition, B10.A macrophages exhibited a prevalent expression of inducible NO-synthase and SOCS3 (suppressor of cytokine signaling-3), indicating a pro-inflammatory, \"M1-like\" differentiation. In contrast, the elevated expression of arginase-1, found in inflammatory zone-1 (FIZZ1), YM1 (CHI313, chitinase-like lectin), and SOCS1, typical markers of alternatively activated macrophages, indicates a prevalent \"M2-like\" differentiation of A/J macrophages. In conclusion, our data reveal that several mannosyl-recognizing receptors coordinate the apparently paradoxical innate response to paracoccidioidomycosis, in which resistance is initially mediated by alternatively activated phagocytes and tolerance to fungal growth, whereas susceptibility is linked to classically activated macrophages and the efficient control of fungal growth.

In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw's nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients' quality of life.

Candida glabrata is an important pathogen causing invasive infection associated with a high mortality rate. One mechanism that causes the failure of Candida eradication is an increase in regulatory T cells (Treg), which play a major role in immune suppression and promoting Candida pathogenicity. To date, how C. glabrata induces a Treg response remains unclear. Dendritic cells (DCs) recognition of fungi provides the fundamental signal determining the fate of the T-cell response. This study investigated the interplay between C. glabrata and DCs and its effect on Treg induction. We found that C. glabrata β-glucan was a major component that interacted with DCs and consequently mediated the Treg response. Blocking the binding of C. glabrata β-glucan to dectin-1 and complement receptor 3 (CR3) showed that CR3 activation in DCs was crucial for the induction of Treg. Furthermore, a ligand–receptor binding assay showed the preferential binding of C. glabrata β-glucan to CR3. Our data suggest that C. glabrata β-glucan potentially mediates the Treg response, probably through CR3-dependent activation in DCs. This study contributes new insights into immune modulation by C. glabrata that may lead to a better design of novel immunotherapeutic strategies for invasive C. glabrata infection.