Lecture 5 - Monocytes and Macrophages

where are monocytes dervived?

from the bone marrow hematopoietic stem cells via myeloid progenitors; circulate briefly before entering tissues

how are macrophages formed?

differentiate from monocytes once the monocyte enters a tissue; guided by local cytokines and tissue signals

what are some examples of macrophages?

Kupffer cells (liver), microglia (CNS), alveolar macrophages (lung), splenic macrophages

what are the major roles of monocytes/macrophages?

phagocytosis, antigen presentation, cytokine production, and tissue repair

what is the origin of the monocytes?

arise from hematopoietic stem cells in the bone marrow via the myeloid lineagewha

what is the process of monocyte formation?

hematopoietic stem cells to myeloid progenitors to granulocyte-macrophage progenitors to monocyte-dendritic cell progenitors

Monocytes differentiate in ______ and ______ after entering the tissues.

macrophages; dendritic cells

what molecules influence this process

Colony-stimulating factors and inflammatory cytokines - M-CSF, GM-CSF

Monocytes do not _______ in circulation.

proliferate

how is phagocytosis performed

engulf and digest microbes, apoptotic cells, and debris - recognize via PRRs

what is the biological importance of phagocytosis

removes infectious agents, maintains tissue homeostasis by clearing apoptotic cells

how does the antigen presentation process occur?

express MHC II to activate CD4+ T cellswha

what is the significance of antigen presentation?

his helps coordinate differing immune responses, initiates adaptive immune response, bridges innate and adaptive immunity

what are the types of cytokines that macrophages produce

• pro-inflammatory - IL-1B, TNF-a, IL-6, = induce inflammation

  • anti-inflammatory - IL-10, TGF-b = suppresses inflammation signals and aids in tissue repair

what factors are used in tissue repair?

• VEGF - stimulates angiogenesis

• TGF-B = promotes fibroblast activation and ECM deposition

• FGF = supports wound healing and tissue regeneration

what role do M2-polarized macrophages play in wound healing?

dominate in LATE stage inflammation, orchestrating repair and remodeling of damaged tissues

what is macrophage polarization

macrophages can shift their functional programming in response to LOCAL MICROENVIRONMENT - delicate balance

what are the two types of polarized macrophages?

M1 - classically activated

M2 - alternatively activated

how are M1 macrophages induced and what is their function?

induced by IFN-y, LPS

function - high microbicidal activity, inflammation, enhance antigen presentation to T cells

Primary role in immunity - defense against intracellular bacteria, viruses, and fungi; initiation and amplification of cell-mediated immune response

how are M2 macrophages induced and what is their function?

induced by IL-4, IK-13

function - repair, fibrosis, anti-inflammatory cytokine production, parasite defense; focus on tissue damage

primary role in immunity - defense against multicellular parasites; limiting excessive tissue damage from prolonged inflammation, supporting regeneration and fibrosis in chronic tissue injury

what other immune cells do macrophages interact with

T cells, B cells, NK cells and granulocytes

how macrophages interact with T cells?

antigen presentation - MHC Class II to CD4+ T helper cells to activate T cells; cytokine signals - IL-12 to support cell-mediated immunity, IL-6 and TGF-B to influence TH17 differentiation

how do macrophages interact with B cells

modulate activity via cytokines

• indirect = cytokines

• antigen provision - process and present native antigens directly to B cells in lymphoid tissues

• support of antibody production by signaling enhance class-switch recombination in B cells

how do macrophages interact with NK cells?

amplify innate responses - activate each other to form feedback loops

how do macrophages interact with granulocytes?

enhance innate immune response through recruitment via chemokines, activation via secretion of TNF-a primers neutrophils for enhanced microbial killing

dying neutrophils release signals to activate and attract more macrophages

which species has distinct monocyte subsets, which are important in disease like Johne’s

ruminants

in which species are macrophages central to FIP pathogenesis

cats

which species is prone to histiocytic diseases

dogs

in which species do alveolar macrophages dominate airway immunity

horses

what is the clinical relevance of monocytes?

• monocytosis

• defective macrophage function

• cancer

• therapeutic targeting

what causes monocytosis

chronic inflammation and stress leukograms

what does defective macrophage function predispose an animal to

predisposes to infections such as mycobacterium and leishmania

what causes cancer relating to macrophages

tumor-associate macrophages promote immunosuppression

what therapeutic targets are being researched?

immunomodulators, vaccine adjuvants, checkpoint inhibition