Monocytes and macrophages Flashcards
Monocyte nucleus shape
Bean-shape
Blood concentration
10% of circulating cells
Development of monocytes
Begin as hematopoietic cells
To common myeloid progenitor (CMP)
To granulocyte/monocyte progenitor
and finally differentiate into monocyte progenitor.
Classical Monocytes
CD14+ CD16-, typically CCR2+.
Intermediate Monocytes:
CD14+ CD16+, commonly CCR5+.
Patrolling/Non-Classical Monocytes
CD14low CD16+, express CX3CR1+ and CD64+.
Mice, Patrolling Monocytes
Ly6Clow.
Mice, Classical Monocytes:
Ly6Chigh.
Flow Cytometry Markers
Utilized to identify and differentiate between various monocyte populations.
Monocyte Role
Monocytes perform phagocytosis, present antigens, and secrete cytokines.
Monocyte Migration
Can migrate to tissues and transform into macrophages or dendritic cells.
Monocyte maturation
Develop from progenitor cells in the bone marrow through various stages before becoming fully mature monocytes.
How long do monocytes circulate in the blood
Circulate in the blood for 1-3 days before migrating to tissues.
Surface markers of monocytes
CD14,CCR2, CCR5, CX3CR1
CD14 surface marker function
A co-receptor for the detection of bacterial lipopolysaccharides (LPS).
CCR2 surface marker function
A receptor that mediates chemotaxis toward sites of inflammation.
CCR5 surface marker function
Involved in the inflammatory response and may play a role in cell migration and activation.
CX3CR1 surface marker function
A receptor involved in adhesion and migration of monocytes.
Monocyte Differentiation into
two types of macrophages—M1 (pro-inflammatory) and M2 (anti-inflammatory/healing)
Monocyte and Cancer
Ongoing research investigates the role of monocytes in cancer, healing, and as vehicles for drug delivery, human and mouse monocytes serve as models to study immune response and pathology
Balance of M1 and M2
The balance between M1 and M2 can influence the outcome of many diseases. (diseases, or hematological disorders.)
High and low monocyte count
High monocyte counts can indicate chronic inflammation, while low counts may suggest bone marrow suppression or systemic lupus erythematosus (SLE).
Functions of Non-classical/Patrolling Monocytes
Sense tissue damage, involved in tissue repair and angiogenesis.
Scavenge and respond to viruses/nucleic acid via endosomal TLR7/8 with cytokines such as TNF, IL-1β, CCL3.
Scavenge immune complexes and have a role in autoimmunit
how do monocyte scavengers and respond to viruses/nucleic acid
via endosomal TLR7/8 with cytokines such as TNF, IL-1β, CCL3.
Functions of Classical Monocytes
Exhibit antimicrobial activity through phagocytosis.
Produce reactive oxygen species (ROS), nitric oxide (NO), myeloperoxidase (MPO), and Type I Interferons.
Mediate inflammation and leukocyte recruitment, responding to cytokines like IL-1α, TNF, IL-6, IL-8, and CCL2.
Activate T cells due to the presence of MHC class II on their surface.
What does classic monocytes produce
Produce reactive oxygen species (ROS), nitric oxide (NO), myeloperoxidase (MPO), and Type I Interferons.
How do they mediate inflammation and leukocyte recruitment
responding to cytokines like IL-1α, TNF, IL-6, IL-8, and CCL2.
TLR4 ligands
trigger a response in patrolling monocytes
TLR7/8 ligands
prompt a response in classical monocytes.
Ly6C^low and Ly6C^high monocytes have different responses to
TLR4 and TLR7/8 stimulation.
monocyte produce key inflammatory cytokines
like TNF, IL-1β, and CCL3 during this response.
what do Classical monocytes release
They release antimicrobial molecules such as ROS, NO, MPO, and Type I Interferons to neutralize threats.
Classical monocytes function
proficient phagocytes that engulf and destroy pathogens and key players in promoting inflammation and recruiting other leukocytes to sites of infection.
Monocyte and MHC II
Antigen presentation, and different monocyte subsets respond to various TLRs, which recognize distinct pathogen-associated molecular patterns.
TLR4
induces a pro-inflammatory reaction in patrolling monocytes.
TLR7/8
Detects viral RNA within endosomes.
What are the stimuli associated with the M1 macrophage phenotype?
LPS, IFNγ, TNFα.
What are the biomarkers associated with the M1 macrophage phenotype?
TNF, IL-1β, IL-6, IL-12, IL-23, iNOS, COX-2, CCR7
What are the functions associated with the M1 macrophage phenotype?
Associated with type 1 inflammation, antigen presentation, and angiogenesis.
What are the stimuli associated with the M2a macrophage phenotype?
IL-4, IL-13
What are the biomarkers associated with the M2a macrophage phenotype?
TGFβ, arginase-1, Ym1, Fizz1.
What are the functions associated with the M2a macrophage phenotype?
with type 2 inflammation, eosinophil recruitment, stabilization of neovascularization.
What are the stimuli associated with the M2b macrophage phenotype?
immune complexes, LPS
What are the biomarkers associated with the M2b macrophage phenotype?
L-1β, IL-6, CCL1, CXCL1, CCL2
What are the stimuli, biomarkers, and functions associated with the M2b macrophage phenotype?
antigen presentation, immune regulation.
What are the stimuli associated with the M2c macrophage phenotype?
IL-10, glucocorticoids, TGFβ1
What are the stimuli, biomarkers, and functions associated with the M2c macrophage phenotype?
CD163, SOCS3, VEGF, MMP9
What are the stimuli, biomarkers, and functions associated with the M2c macrophage phenotype?
tissue remodelling, anti-inflammatory properties, and phagocytosis
What are the stimuli associated with the M2d macrophage phenotype?
TLR agonists, IL-6, A2R agonist, tumor microenvironment
What are the biomarkers associated with the M2d macrophage phenotype?
VEGF, IL-10, IL-12, NO2.
What are the functions associated with the M2d macrophage phenotype?
Associated with tumor-associated immune regulation and angiogenesis.
Endothelial Activation (for monocyte activation)
CD4+ T cells secrete CXCL10; endothelial cells express VCAM1.
Recruitment(for monocyte activation)
Neutrophils and monocytes migrate to the site.
monocyte activation
Monocytes differentiate into macrophages, expressing CCR2, CX3CR1, and produce IL-1β, TNFα.
Fibroblast ACtivation
Driven by IL-13 from CD4+ T cells.
Macrophage tissue repair
facilitate growth of new tissue and differentiate into M2 phenotype promoting healing.
Where do tissue-resident macrophages originate from?
originate from embryonic precursors, particularly from the yolk sac and fetal liver monocytes, which migrate to tissues early in development
Subtypes of monocytes
classical, intermediate, and non-classical/patrolling monocytes, each with distinct surface markers and functions.
differentiation Classical monocytes (CD14+ CD16-)
migrate through the blood and can differentiate into various macrophage subtypes in tissues.
What functions do tissue macrophages serve?
phagocytize microbes and dead cells, secrete cytokines that modulate immune responses, present antigens to T cells, and are involved in tissue remodeling and repair.
What is the typical size of a monocyte and its nucleus shape?
Monocytes are typically 10-15μm in diameter with a characteristic bean-shaped nucleus.
What factors differentiate Ly6Clow and Ly6Chigh monocytes in their response to TLR stimulation?
Ly6Clow responds differently to TLR4 and TLR7/8 stimulation, with TLR4 inducing a pro-inflammatory response and TLR7/8 making classical monocytes respond.
What are the three populations of monocytes in humans and their markers?
Classical (CD14+ CD16-), Intermediate (CD14+ CD16+), and Patrolling/Non-classical (CD14low CD16+).
Describe the transition of classical monocytes in tissue.
Classical monocytes can transition to patrolling monocytes. They are the first to arrive at an injury site and later become CX3CR1 positive, a transition driven by IL-4/IL-10 for repair.
What are the two origins of tissue-resident macrophages?
Embryonic origin, where macrophages are established prenatally, and bone marrow hematopoiesis, leading to monocyte-derived macrophages.
What are DOMs in the context of macrophage function?
DOMs refer to Delayed Onset Muscle Soreness, which is associated with the production of pro-inflammatory cytokines by macrophages
What are the unique functions of tissue-resident macrophages?
What are the unique functions of tissue-resident macrophages?
What are Synovial Tissue Macrophages (STMs)
STMs are specialized macrophages forming a protective layer in the synovial membrane of joints.
Where do STMs arise from
fetal hematopoietic stem cells during embryonic development, indicating early specialization.
STM function
maintain joint homeostasis and prevent autoimmune reactions, act as a crucial barrier to infection and are implicated in the pathogenesis and resolution of arthritis.
STMs
Synovial Tissue Macrophage
Role of Macrophage Polarization in Rheumatoid Arthritis (RA)
macrophages can exhibit M1 or M2 polarization, contributing to either inflammation (M1) or healing (M2)
M1 in RA
pro-inflammatory and often exacerbate the destruction of joint tissue.
What does it mean that macrophages are heterogeneous?
existence of diverse macrophage subtypes, each with unique functions and phenotypic markers.
M2 in RA
facilitate tissue repair and regeneration, reducing inflammation.
Balance of M1 and M2 in RA
influences the progression and resolution of RA symptoms.
why is macrophages are heterogeneous essential
This plasticity is vital for responding appropriately to various pathological conditions.
How do monocyte-derived and tissue-resident macrophages differentiation?
Monocyte-derived macrophages can differentiate into tissue-resident macrophages adapting to the needs of the local microenvironment.
Tissue-resident macrophages originate from
both the embryo and the bone marrow, allowing a combination of innate immune memory and adaptive response.
Integration of monocyte-derived and tissue-resident macrophages
Coordinated immune response, ranging from initial inflammation to subsequent healing processes.
Their collective activities are crucial in tissue repair, inflammation resolution, and maintenance of tissue homeostasis.
How do macrophages assist in the resolution of inflammation
secreting anti-inflammatory cytokines and growth factors such as VEGF-A, promoting angiogenesis.
How do Tissue repair macrophages help resolve inflammation
display receptors like IL-4R and CD206 and can derive from both local proliferation and recruitment of circulating monocytes.
What is Macrophage Polarization?
dynamic changes in macrophage function in response to environmental cues, resulting in diverse phenotypes: pro-inflammatory (M1) or anti-inflammatory (M2).
M1 macrophages are stimulated by
LPS and IFNγ, leading to an inflammatory response critical for defense against pathogens.
M2 macrophages, induced by
IL-4 and IL-13, play roles in tissue repair, immune regulation, and resolution of inflammation.
What characterizes pro-inflammatory (M1) macrophages?
produce inflammatory cytokines (TNF-α, IL-1β, IL-6), reactive nitrogen and oxygen species, and present antigens to T cells, fueling the inflammatory response.
M1 involved in
initial defense mechanism against pathogens and are associated with the progression of inflammatory diseases.
M1 express
high levels of surface molecules like CSF1R and produce enzymes such as iNOS.
What characterizes anti-inflammatory (M2) macrophages?
contribute to the resolution phase of inflammation, tissue remodeling, and repair, as well as the maintenance of homeostasis.
M2 produce
anti-inflammatory cytokines like IL-10 and growth factors including TGF-β to facilitate healing.
M2 arise from
arious signals such as IL-4, IL-13, and immune complexes, influencing their specific roles in the immune response.
How do macrophages diversify and specialize?
Macrophages exhibit remarkable plasticity, with the ability to switch between M1 and M2 phenotypes depending on the microenvironmental context.
Macrophage specialization
influenced by factors such as tissue of residence, length of stay in the tissue, and the nature of the inflammatory respons
What is TGF-β and its role in the immune system?
regulator in wound healing, fibrosis, and immune cell regulation, helping to suppress inflammation and facilitate tissue remodeling.
TGF-β
Transforming Growth Factor-Beta
Function of VEGF in tissue repair?
stimulates angiogenesis, the formation of new blood vessels, crucial for supplying nutrients and oxygen to healing tissues.
VEGF
Vascular Endothelial Growth Factor
FGF
Fibroblast Growth Factor
role of FGF in the healing process?
involved in cell proliferation and differentiation during wound healing and tissue regeneration.
What does PDGF do in tissue repair?
recruits cells like fibroblasts to the injury site to proliferate and produce extracellular matrix, contributing to the repair.
PDGF
Platelet-Derived Growth Factor
How does EGF contribute to tissue regeneration?
promotes cell growth and differentiation, especially epithelial cell repair, aiding in the healing of wounds.
EGF
Epidermal Growth Factor
IGF
Insulin-Like Growth Factor
IGF’s importance in muscle and bone repair?
aids in cell survival and growth, playing a key role in muscle and bone repair.
Macrophages contribute to tissue repair and regeneration by releasing a variety of growth factors;
TGF-β - Transforming Growth Factor-Beta
VEGF - Vascular Endothelial Growth Factor
FGF - Fibroblast Growth Factor
PDGF - Platelet-Derived Growth Factor
EGF - Epidermal Growth Factor
IGF - Insulin-Like Growth Factor
Necrotic EC
necrotic endothelial cells
Necrotic EC
death of cells in an organ or tissue due to disease, injury, or failure of the blood supply.
