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1.
Immun Ageing ; 18(1): 29, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154615

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. OBJECTIVES: AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. RESULTS: We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. CONCLUSION: Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

2.
Commun Biol ; 4(1): 401, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767430

RESUMO

Vitamin D deficiency remains a global concern. This 'sunshine' vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.


Assuntos
Calcitriol/metabolismo , Imunidade Inata/fisiologia , Imunoglobulinas/metabolismo , Macrófagos/metabolismo , Receptores de Complemento 3b/genética , Regulação para Cima/imunologia , Receptores de Complemento 3b/metabolismo
3.
CNS Drugs ; 34(7): 673-695, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32458360

RESUMO

Alzheimer's disease (AD) is the most prevalent dementia in the world. Its cause(s) are presently largely unknown. The most common explanation for AD, now, is the amyloid cascade hypothesis, which states that the cause of AD is senile plaque formation by the amyloid ß peptide, and the formation of neurofibrillary tangles by hyperphosphorylated tau. A second, burgeoning theory by which to explain AD is based on the infection hypothesis. Much experimental and epidemiological data support the involvement of infections in the development of dementia. According to this mechanism, the infection either directly or via microbial virulence factors precedes the formation of amyloid ß plaques. The amyloid ß peptide, possessing antimicrobial properties, may be beneficial at an early stage of AD, but becomes detrimental with the progression of the disease, concomitantly with alterations to the innate immune system at both the peripheral and central levels. Infection results in neuroinflammation, leading to, and sustained by, systemic inflammation, causing eventual neurodegeneration, and the senescence of the immune cells. The sources of AD-involved microbes are various body microbiome communities from the gut, mouth, nose, and skin. The infection hypothesis of AD opens a vista to new therapeutic approaches, either by treating the infection itself or modulating the immune system, its senescence, or the body's metabolism, either separately, in parallel, or in a multi-step way.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Placa Amiloide/tratamento farmacológico , Placa Amiloide/metabolismo
4.
Front Immunol ; 10: 2892, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31921153

RESUMO

The B7 family-related protein V-set and Ig containing 4 (VSIG4), also known as Z39Ig and Complement Immunoglobulin Receptor (CRIg), is the most recent of the complement receptors to be identified, with substantially distinct properties from the classical complement receptors. The receptor displays both phagocytosis-promoting and anti-inflammatory properties. The receptor has been reported to be exclusively expressed in macrophages. We now present evidence, that CRIg is also expressed in human monocyte-derived dendritic cells (MDDC), including on the cell surface, implicating its role in adaptive immunity. Three CRIg transcripts were detected and by Western blotting analysis both the known Long (L) and Short (S) forms were prominent but we also identified another form running between these two. Cytokines regulated the expression of CRIg on dendritic cells, leading to its up- or down regulation. Furthermore, the steroid dexamethasone markedly upregulated CRIg expression, and in co-culture experiments, the dexamethasone conditioned dendritic cells caused significant inhibition of the phytohemagglutinin-induced and alloantigen-induced T cell proliferation responses. In the alloantigen-induced response the production of IFNγ, TNF-α, IL-13, IL-4, and TGF-ß1, were also significantly reduced in cultures with dexamethasone-treated DCs. Under these conditions dexamethasone conditioned DCs did not increase the percentage of regulatory T cells (Treg). Interestingly, this suppression could be overcome by the addition of an anti-CRIg monoclonal antibody to the cultures. Thus, CRIg expression may be a control point in dendritic cell function through which drugs and inflammatory mediators may exert their tolerogenic- or immunogenic-promoting effects on dendritic cells.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Imunidade Celular/genética , Receptores de Complemento/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Biomarcadores , Técnicas de Cocultura , Citocinas/metabolismo , Humanos , Imunomodulação , Imunofenotipagem , Receptores de Complemento/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Sci Rep ; 7(1): 4050, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28642550

RESUMO

Complement Receptor Immunoglobulin (CRIg), selectively expressed by macrophages, plays an important role in innate immunity by promoting phagocytosis of bacteria. Thus modulation of CRIg on macrophages by cytokines can be an important mechanism by which cytokines regulate anti-microbial immunity. The effects of the cytokines, tumor necrosis factor, transforming growth factor-ß1, interferon-γ, interleukin (IL)-4, IL-13, IL-10, IL-1ß, IL-6, lymphotoxin-α, macrophage-colony stimulating factor (M-CSF) and GM-CSF on CRIg expression were examined in human macrophages. We demonstrated that cytokines regulated the CRIg expression on macrophages during their development from monocytes in culture at the transcriptional level using qPCR and protein by Western blotting. Both CRIg spliced forms (Long and Short), were similarly regulated by cytokines. Direct addition of cytokines to matured CRIg+ macrophages also changed CRIg mRNA expression, suggesting that cytokines control macrophage function via CRIg, at two checkpoints. Interestingly the classical complement receptors, CR3 and CR4 were differentially regulated by cytokines. The changes in CRIg but not CR3/CR4 mRNA expression correlated with ability to phagocytose Candida albicans by macrophages. These findings suggest that CRIg is likely to be a control point in infection and immunity through which cytokines can mediate their effects, and is differentially regulated from CR3 and CR4 by cytokines.


Assuntos
Candida albicans/imunologia , Citocinas/metabolismo , Expressão Gênica , Macrófagos/imunologia , Macrófagos/microbiologia , Fagocitose/imunologia , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Candidíase/etiologia , Candidíase/metabolismo , Citocinas/farmacologia , Humanos , Mediadores da Inflamação , Integrina alfaXbeta2/genética , Antígeno de Macrófago 1/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Fagocitose/efeitos dos fármacos
6.
J Immunol ; 194(6): 2855-61, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25687755

RESUMO

The complement receptor Ig (CRIg) is selectively expressed by macrophages. This receptor not only promotes the rapid phagocytosis of bacteria by macrophages but also has anti-inflammatory and immunosuppressive functions. Previous findings have suggested that protein kinase C (PKC) may be involved in the regulation of CRIg expression in human macrophages. We have now examined the role of PKCα in CRIg expression in human monocyte-derived macrophages (MDM). Macrophages nucleofected with plasmid containing short hairpin RNA against PKCα showed markedly reduced expression of PKCα, but normal PKCζ expression, by Western blotting analysis, and vice versa. PKCα-deficient MDM showed increased expression of CRIg mRNA and protein (both the long and short form), an increase in phagocytosis of complement-opsonized Candida albicans, and decreased production of TNF-α and IL-6. TNF-α caused a marked decrease in CRIg expression, and addition of anti-TNF mAb to the TNF-α-producing MDMs increased CRIg expression. PKCα-deficient macrophages also showed significantly less bacterial LPS-induced downregulation of CRIg. In contrast, cells deficient in PKCα showed decreased expression of CR type 3 (CR3) and decreased production of TNF-α and IL-6 in response to LPS. MDM developed under conditions that increased expression of CRIg over CR3 showed significantly reduced production of TNF-α in response to opsonized C. albicans. The findings indicate that PKCα promotes the downregulation of CRIg and upregulation of CR3 expression and TNF-α and IL-6 production, a mechanism that may promote inflammation.


Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Proteína Quinase C-alfa/imunologia , Receptores de Complemento/imunologia , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacologia , Western Blotting , Candida albicans/imunologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Adesão Celular/imunologia , Células Cultivadas , Dexametasona/imunologia , Dexametasona/farmacologia , Regulação para Baixo/imunologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Antígeno de Macrófago 1/genética , Antígeno de Macrófago 1/imunologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Interferência de RNA , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
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