Lecture 5 - Monocytes and Macrophages

Where do monocytes and macrophages come from?

hematopoetic cells in bone marrow

What are monocytes?

mononuclear leukocytes w/ a kidney shaped nucleus

- HSC to common myeloid progenitor to GMP to monoblast to promonocyte to monocyte

- cyrulates for 1 to 3 days (cannot proliferate, but can differentiate)

What do monocytes differentiate into?

macrophages OR monocyte derived DCs

What drives monocyte differentiation to macrophages?

1. M-CSF

2. GM-CSF

What influences monocyte differentiation to monocytes?

1. tissue signals (cytokines and GFs)

2. infcetion/damage

What can macrophages polarize to?

tissue macrophage M1 or M2 dependent on local cytokines

What are resident macrophages?

1. embryonic/fetal derrived

2. self renewing (no monocyte input needed)

What are inflammatory/tissue macropahges?

regularly replenished from circulating monocytes

What are the functions of macrophages?

1. phagocytosis

2. antigen presentation

3. cytokine production

4. tissue repair and remodeling

What is macrophage phagocytosis and steps?

1. recognition and binding - using PRRs, opsonin receptors, complement receptors

2. engulfment - formation of phagosome

3. digestion - phagasome fuses with lysosomes into PHAGOLYSOSOME

4. clears pathogens, apoptotic cells, and maintains tissue homeostasis

What is macrophage antigen presentation and types?

presentation of antigens by MHC on cell surface

MHC 1 - SELF antigens recognized by CD8+ and T cells (cytotoxic)

MHC 2 - NON SELF antigens, presented to CD4+ and Th cells

What happens after macrophage is activated?

1. upregulation of MHC II

2. upregulation of CD80/86 to fully activate T cells

3. bridge innate and adaptive immunity

What is MHC?

molcules on the cell surface that can carry self or nonself processed antigens

What cells have MHC II?

on antigen presenting cells like macrophages and DCs, from engulfed proteins

What is macrophage cytokine production?

secreting a wide variety of cytokines that help shape immune responses

What is macrophage pro inflammatory functions?

IL -1B - promotes fever, WBC recruitment, and acute phase protein production

TNF-a - increases vascular permeability, activates endothelium, and enhances WBC trafficking

IL-6 - induces acute pahse response and supports B cell differentiation

What is macrophage anti inflammatory functions?

IL-10 - supresses pro inflamamtory cytokine production, resolution of inflamamtion

TGF - B - aids in tissue repair, fibrosis, and immune regulation

What is macrophage tissue repair and remodeling?

1. angiogenesis

2. fibrolast activation

3. ECM deposition,

4. wound healing

What is mcrophage role in GF secretion?

VEGF - stimulates angiogenesis

TGF -B - promotes fibroblast activation and extracellular matrix deposition

FGF - supports wound healing and tissue regeneration

What is macrophage role in healing?

M2 - direct repair and remodelling

What is macrophage poalrization?

they are highly adaptable cells that can shift their functional programming in response to LOCAL MICROENVIRONMENT (M1 or M2)

What to know about M1 macrophages

CLASSICAL

Stimuli - IFN-y, LPS

1. produce ROS/NO, proinflammtory cytokines

2. defense against intracellular bacteria, viruses, fungi

What to know about M2 macrophages?

ALTERNATIVE

Stimuli - IL-4 and IL-13

1. produce IL-10, TGF-B

2. help with wound healing, parasite clearence, and fibrosis

What are macrophage interactions?

they are NOT solitary defender and influence BOTH innate and adaptive immune system

What are macrophages connection to T cells?

present antigens through MHCII and secrete IL-12 and will recieve IFN-y back

What are macrophages connection to B cells?

secrete IL-6, BAFF, and APRIL to ptomote B cell survival, plasma cell differentiation, and antibody class switching

What are macrophages connection to NK cells?

activated by IL-12/18 and NK IFN-y will further activate macrophages

What are macrophages work with granulocytes?

release chemokines to recruit neutrophils/eosinophils (TNF-a primes neutrophils)

Role with ruminants

key in Johne's dz

Role with cats

FIP, coronavirus replicates in macrophages

Role in dogs

histiocytic dz

Role in horses

alveolar macrophages dysregulation leads to inflammatory airway dz

What is the clinical relevance of macrophages?

monocytosis - chronic inflammation, granuluma dz

defective macrophages - incraesed succesptibility to intracellular pathogens

cancer - TAMs show M2 linkage

therapeutic targets - shift TAMS from M2 to M1 , vaccine adjuvuncts, target PD-L1 expression