4 research outputs found
Consequências da indução C4BP (ß-) em macrófagos derivados de monócitos
Mestrado em BioquĂmicaAs doenças inflamatĂłrias sĂŁo a principal causa de morbilidade e
mortalidade em todo o mundo e representam um grande desafio na área das
ciências biomédicas. Sendo assim, o desenvolvimento de terapias é essencial e,
para tal, uma compreensĂŁo do funcionamento do sistema imune do hospedeiro Ă©
fundamental.
A ativação do sistema complemento representa o passo inicial para o
desenvolvimento de uma resposta imune-infamatĂłria protetiva contra o dano.
Porém, uma ativação inapropriada poderá danificar o tecido do hospedeiro, sendo
potencialmente destrutivo, podendo causar diversas doenças.
A proteĂna solĂşvel responsável pela inibição do sistema complemento,
C4b-binding protein (C4BP), atua tanto na regulação da via clássica como na de
lectina do sistema complemento, modificando a atividade da C3 convertase e
prevenindo, assim, a expressĂŁo exagerada deste sistema e, consequentemente, o
dano tecidual no hospedeiro. A C4BP Ă© uma grande glicoproteĂna plasmática
oligomérica, composta por sete cadeias α idênticas e uma única cadeia β, que
forma três oligómeros plasmáticos devido a diferentes composições de
subunidades. A isoforma C4BP sem a cadeia β, C4BP (β-), parece apresentar uma
função direta na modulação de respostas imunes adaptativas. Estudos recentes no
laboratório demonstraram que a C4BP (β-) é capaz de promover um perfil
tolerogĂ©nico e anti-inflamatĂłrio em cĂ©lulas dendrĂticas derivadas de monĂłcitos.
Os macrĂłfagos sĂŁo cĂ©lulas amplamente distribuĂdas do sistema imune
inato que apresentam uma função central na defesa do organismo contra
patĂłgenos invasores e no mantimento da imune homeostase, contribuindo para a
inflamação e promovendo a cura de feridas e reparação de tecidos. São células
dinâmicas que maturam sob a influência de sinais provenientes do
microambiente. Neste estudo, monócitos de sangue periférico humano foram
diferenciados em macrĂłfagos (M0) e, posteriormente, polarizados a fenĂłtipos M1
e M2, utilizando LPS/IFN-Îł, e IL-4, respetivamente. M1 e M2 foram
identificados por citometria de fluxo como CD80+ CD64+ e CD11b+ CD209+,
respetivamente.
A atividade endocĂtica e fagocĂtica foi tambĂ©m investigada dado que os
macrófagos são células altamente fagocitárias. Quando os macrófagos foram
maturados ao fenĂłtipo M1, uma diminuição da capacidade endocĂtica foi
observada, comparando com as células não polarizadas (M0). No entanto, quando
os macrĂłfagos foram polarizados ao fenĂłtipo M2, nĂŁo foi evidente uma
diminuição da expressĂŁo da atividade endocĂtica, comparando com M0,
evidenciando, assim, que M2 são células com elevada capacidade endocitária.
Além disto, macrófagos M2 também demonstraram uma capacidade fagocitária
superior a macrĂłfagos M1. E concluindo, a proteĂna C4BP (β-) reduziu a
atividade endocĂtica dos macrĂłfagos, embora nĂŁo tenha apresentado qualquer
efeito na atividade fagocĂtica.
Alterações no fenótipo e função dos macrófagos pode estar associado
com uma variedade de doenças autoimunes, incluindo o lúpus eritematoso
sistémico. Esta enfermidade é caracterizada por várias manifestações desde a pele
e lesões nas mucosas a danos severos nos rins e no sistema nervoso central.
Assim, marcadores da doença mais eficazes, risco, atividade da doença e
gravidade dos danos nos órgãos poderão facilitar o diagnóstico prévio e orientar
o paciente para uma terapia adequada; dado que os tratamentos atuais nĂŁo sĂŁo
totalmente eficientes. Por esta razão, o desenvolvimento de novas estratégias é
fundamental, e a atividade anti-inflamatória e imunomodeladora da C4BP (β-)
poderá representar uma opção terapêutica para esta doença autoimune.Inflammatory diseases are the leading cause of morbidity and mortality
worldwide and are a major challenge for the biomedical sciences. The
development of therapeutics is essential and this requires an understanding of the
host immune system.
The activation of the complement system represents the initial step in the
protective immune-inflammatory response against damage. Nevertheless, an
inappropriate activation may also damage the host tissue, being potentially
destructive and causing several diseases.
The soluble complement inhibitor C4b-binding protein (C4BP) acts in the
regulation of the classical and lectin pathways of the complement system,
modifying the activity of the C3 convertase, and preventing complement over
activation and host tissue damage. C4BP is a large oligomeric plasma
glycoprotein, composed by seven identical α-chains and a single β-chain, which
forms three plasma oligomers with different subunit composition. The C4BP
isoform without the β-chain, C4BP (β-) seems to play a direct role in the
modulation of adaptive immune responses. Recent studies in the lab
demonstrated that C4BP (β-) is able to promote a tolerogenic and antiinflammatory
profile on monocyte-derived dendritic cells.
Macrophages are widely distributed innate immune cells that play central
roles in host defense against invading pathogens and in maintaining the immune
homeostasis, contributing to inflammation, and promoting wound healing and
tissue repair. They are dynamic cells that mature under the influence of signals
from the local microenvironment. In this study, human peripheral blood monocytes were differentiated into
uncommitted macrophages (M0) and then polarized to M1 and M2 phenotypes
using LPS and IFN-Îł, and IL-4, respectively. M1 and M2 were identified by flow
cytometry as CD80+ CD64+ and CD11b+ CD209+, respectively.
The endocytic and phagocytic activity was also investigated, since
macrophages are highly phagocytic cells. When macrophages were matured to
M1 phenotype, a downregulation of the endocytic activity was observed,
compared to the unpolarized cells. In contrast, when macrophages were polarized
to M2 phenotype, no downregulation of endocytic activity compared with M0
was evidenced, showing that M2 are highly endocytic cells. Moreover, M2
macrophages showed a higher phagocytic activity than M1 macrophages. Finally,
C4BP (β-) reduced the endocytic activity of macrophages, although did not have
any effect on its phagocytic activity.
Alterations in the phenotype and function of macrophages can be
associated with a variety of autoimmune disorders, including systemic lupus
erythematosus. This disorder is characterized by several manifestations from the
skin to mucosal lesions, to severe damage in the kidneys and in the central
nervous system. More effective markers of the disease, risk, disease activity;
severity of organ damage and of the outcomes would facilitate earlier diagnosis
and guide appropriately targeted therapy; since the actual treatments are not fully
effective. For this reason, the development of new strategies is fundamental, and
the anti-inflammatory and immunomodulatory activity of C4BP (β-) can
represent an effective therapeutic option to this autoimmune disease
Pervasive gaps in Amazonian ecological research
Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4
While the increasing availability of global databases on ecological communities has advanced our knowledge
of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In
the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of
Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus
crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced
environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian
Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by
2050. This means that unless we take immediate action, we will not be able to establish their current status,
much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio
Pervasive gaps in Amazonian ecological research
Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost