Role of Macrophages

Slide 1 · Role of Macrophages

Origins • activation • chronic inflammation • tissue repair

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes: Explain what macrophages do

Identify developmental sources and tissue-specific macrophage populations.

Explain recruitment, activation and effector functions in chronic inflammation.

Connect macrophage–T cell signaling to tissue injury, repair and granulomas.

Lineage and recruitment

Activation and effector functions

Pathologic outcomes

SCHEMATIC

Slide 3 · Chronic inflammation combines three simultaneous processes

Prolonged inflammation often continues for weeks or months.

Tissue injury coexists with the cellular inflammatory response.

Healing reactions occur at the same site, frequently with fibrosis.

Inflammation

Tissue injury

Repair / fibrosis

SCHEMATIC

Slide 4 · Why chronic inflammation persists

Persistent microbes resist elimination and maintain inflammatory stimulation.

Inappropriate immune reactions can amplify injury against self or environmental antigens.

Nondegradable or toxic material may provide a continuing stimulus.

Resistant microorganisms

Immune dysregulation

Toxic / inert particles

Persistent stimulus

SCHEMATIC

Slide 5 · The histologic triad of chronic inflammation

Mononuclear infiltrates include macrophages, lymphocytes and plasma cells.

Tissue destruction results from the agent, inflammatory cells, or both.

Angiogenesis and connective-tissue deposition mark attempted healing.

Mononuclear cells

Parenchymal injury

Fibrosis / angiogenesis

SCHEMATIC

Slide 6 · Macrophages are central—not merely scavengers

They eliminate microbes and damaged tissues by phagocytosis.

They secrete cytokines and growth factors that change neighboring cell behavior.

They communicate with T lymphocytes and organize the tissue response.

Removal

Inflammation

T-cell activation

Repair

Macrophage

SCHEMATIC

Slide 7 · One cell population can protect and damage tissue

Microbicidal products support host defense.

Excessive or inappropriate activation can injure normal tissue.

Growth factors also initiate the repair response after injury.

Eliminate danger

Collateral injury

Coordinate repair

SCHEMATIC

Slide 8 · The mononuclear phagocyte system

Monocytes are circulating cells of the macrophage lineage.

Macrophages are resident or recruited tissue phagocytes.

The historical term “reticuloendothelial system” is imprecise.

Circulating monocyte

Tissue macrophage

Phagocytosis and signaling

SCHEMATIC

Slide 9 · Two developmental routes contribute macrophages

Hematopoietic stem cells in bone marrow generate circulating monocytes.

Embryonic yolk sac and fetal liver provide precursors to selected resident populations.

Origin depends on tissue and inflammatory context.

Postnatal pathway

Bone marrow stem cell

Blood monocyte

Inflammatory macrophage

Embryonic pathway

Yolk sac / fetal liver

Early tissue seeding

Long-lived resident pool

SCHEMATIC

Slide 10 · Bone marrow-derived macrophage development

Committed marrow precursors produce monocytes.

Monocytes enter blood before crossing vascular endothelium.

Differentiation within tissues yields macrophages.

Marrow progenitor

Blood monocyte

Tissue entry

Macrophage

SCHEMATIC

Slide 11 · Embryonic precursors establish resident populations

Progenitors arise early in the yolk sac or fetal liver.

They enter developing organs and establish tissue macrophage populations.

Some resident populations are maintained long term.

Yolk sac / fetal liver

Developing organ

Resident macrophage

SCHEMATIC

Slide 12 · Inflammatory and resident macrophages: Origins differ

Inflamed tissues often contain recruited monocyte-derived macrophages.

The brain, liver and lung contain populations seeded during development.

A tissue label does not by itself identify the origin of every macrophage in disease.

Inflammatory influx

Blood monocytes

Endothelial emigration

Tissue differentiation

Tissue residence

Early organ colonization

Established tissue pool

Long-term persistence

SCHEMATIC

Slide 13 · Different organs assign different macrophage names

Location

Macrophage name

Liver

Kupffer cell

Brain / CNS

Microglia

Lung alveolus

Alveolar macrophage

Spleen / lymph-node sinuses

Sinus histiocyte

Kupffer cells are liver macrophages.

Microglia are macrophages in the central nervous system.

Alveolar macrophages reside in the lung; Sinus histiocytes occur in lymphoid organs.

Slide 14 · Macrophages are also dispersed in connective tissues

They are present beyond specialized organ compartments.

Skin and intestinal tissues can receive monocyte-derived macrophages.

Location and recent recruitment together shape local macrophage composition.

Connective tissue

Skin

Intestinal tract

Specialized organs

Tissue macrophages

SCHEMATIC

Slide 15 · Monocytes and macrophages have different kinetics

Blood monocytes have an approximate half-life of one day in the cited text.

Tissue macrophages may survive for months to years.

This difference permits prolonged local macrophage activity.

Blood monocytes

Circulating compartment

Approx. 1-day half-life

Source for tissue influx

Tissue macrophages

Extravascular compartment

Months–years lifespan possible

Persistent local effector functions

SCHEMATIC

Slide 16 · Macrophages can dominate after the early response

Monocytes begin entering inflamed tissues relatively early.

Within about 48 hours, macrophages may become the predominant cell type.

Timing is a pattern, not a universal diagnostic cutoff.

Early acute response

Monocyte entry

Macrophage-rich infiltrate

SCHEMATIC

Slide 17 · How monocytes reach injured tissue

The processes depend on endothelial adhesion molecules.

Chemotactic factors guide monocytes toward the inflammatory stimulus.

After exiting blood, monocytes differentiate into tissue macrophages.

Vascular adhesion

Extravasation

Chemotaxis

Differentiation

SCHEMATIC

Slide 18 · Two processes can maintain macrophage accumulation

Continued recruitment replenishes macrophages from the circulation.

Local macrophage proliferation can enlarge the tissue population.

Persistent accumulation helps maintain chronic inflammation.

Continuous recruitment

Local proliferation

Tissue persistence

Macrophage pool

SCHEMATIC

Slide 19 · Macrophages may disappear after the stimulus resolves

Removal of the irritant permits the inflammatory response to subside.

Some macrophages die; Others depart through lymphatics and lymph nodes.

Failure to remove the stimulus favors persistence.

Stimulus eliminated

Inflammation subsides

Death or lymphatic exit

Less macrophage accumulation

Stimulus persists

Ongoing recruitment

Possible local proliferation

Sustained macrophage activation

SCHEMATIC

Slide 20 · Phagocytosis removes microbes and dead tissue

Macrophages are professional phagocytes.

Targets include infectious agents and necrotic cellular material.

Clearance is both defensive and preparatory for repair.

Microbe / debris

Engulfment

Intracellular destruction

Cleaner tissue bed

SCHEMATIC

Slide 21 · Activated macrophages deploy microbicidal effectors

Classically activated macrophages produce reactive oxygen species (ROS).

Nitric oxide (NO) contributes to microbial killing.

Lysosomal enzymes digest material taken into phagocytic compartments.

ROS

NO

Lysosomal enzymes

Microbial killing

SCHEMATIC

Slide 22 · The same effector products can injure host tissue

ROS, NO and enzymes are useful in antimicrobial defense.

Excess activation can damage normal tissue components.

Collateral destruction explains part of the morphology of chronic inflammation.

Sustained activation

Toxic mediators

Host tissue injury

SCHEMATIC

Slide 23 · Macrophages transmit inflammation by cytokines

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are examples.

Chemokines direct additional leukocyte recruitment.

These mediators help initiate and propagate inflammatory reactions.

TNF

IL-1

Chemokines

Activated macrophage

SCHEMATIC

Slide 24 · Chemokines reinforce leukocyte recruitment

Activated macrophages contribute chemotactic mediator signals.

Newly arriving leukocytes can expand the inflammatory infiltrate.

Recruitment creates a potential positive feedback mechanism.

Macrophage activation

Chemokines

Leukocyte influx

Continued inflammation

↺ Reinforcing feedback

SCHEMATIC

Slide 25 · Eicosanoids add another mediator class

Macrophages can generate eicosanoid inflammatory mediators.

They act alongside protein mediators such as cytokines.

Macrophage influence therefore extends beyond direct phagocytosis.

Protein mediators

TNF

IL-1

Chemokines

Lipid mediators

Eicosanoids

Act with cytokines

Inflammatory signaling

SCHEMATIC

Slide 26 · Macrophage-derived signals have distinct recipients

Leukocytes respond to recruitment and activation mediators.

T lymphocytes respond to antigen presentation and cytokines.

Fibroblasts and reparative cells respond to growth factors.

Recruited leukocytes

T lymphocytes

Fibroblasts / repair cells

Macrophage signals

SCHEMATIC

Slide 27 · Antigen presentation links innate and adaptive responses

Macrophages display antigens to T lymphocytes.

Costimulatory molecules participate in T-cell activation.

Inflammatory cytokines, including IL-12, strengthen this communication.

Antigen-bearing macrophage

T-cell recognition

Activated T cell

SCHEMATIC

Slide 28 · Macrophages and T cells activate one another

Macrophages present antigen and secrete T-cell-stimulating cytokines.

Activated T cells secrete macrophage-activating signals.

This bidirectional circuit sustains chronic inflammation.

Antigen presentation

T-cell activation

IFN-γ and cytokines

Macrophage activation

↺ Reinforcing feedback

SCHEMATIC

Slide 29 · IL-12 is part of the macrophage-to-T-cell arm

Activated macrophages can produce IL-12.

Along with antigen display and costimulation, IL-12 supports T-cell responses.

The responding T cells can further influence macrophage behavior.

Macrophage

Antigen + IL-12

T-cell response

Macrophage signals

SCHEMATIC

Slide 30 · T-cell subsets deliver different macrophage signals

T-cell setting

Principal signal

Relevant result

Th1

IFN-γ

Classical macrophage activation

Th2

IL-4 / IL-13

Alternative activation

Th17

IL-17-linked chemokines

Leukocyte recruitment

Th1 cells generate IFN-γ, promoting classical activation.

Th2-associated IL-4 and IL-13 promote alternative activation.

Th17-driven chemokine pathways favor further neutrophil and monocyte recruitment.

Slide 31 · Activation states reflect external signals

Different stimuli change macrophage effector programs.

Classical and alternative activation as broad pathways.

These are conceptual poles rather than exhaustive cell subsets.

Classical / M1-like

Microbial products

IFN-γ / foreign material

Killing + inflammation

Alternative / M2-like

IL-4 / IL-13

Resolution and repair

Less microbicidal emphasis

SCHEMATIC

Slide 32 · Classical activation has several initiating stimuli

Microbial endotoxin engages toll-like receptors (TLRs) and related sensors.

IFN-γ supplied by T cells is a major immune signal.

Crystals and particulate material may also induce classical activation.

Microbial products / TLRs

Th1-derived IFN-γ

Crystals / particles

Classical activation

SCHEMATIC

Slide 33 · Microbial sensing promotes classical activation

Bacterial products are detected by innate immune receptors such as TLRs.

Activation boosts microbicidal machinery and inflammatory mediator release.

The response is useful when a microbial threat must be destroyed.

Microbial material

TLR sensing

Classical activation

Microbial killing

SCHEMATIC

Slide 34 · IFN-γ bridges Th1 immunity and macrophage killing

Th1 cells produce interferon-γ (IFN-γ).

IFN-γ strongly activates macrophages by the classical pathway.

This signaling underlies important cell-mediated immune defenses.

Activated Th1 cell

IFN-γ

Macrophage activation

Microbial defense

SCHEMATIC

Slide 35 · Particulate matter can drive macrophage activation

Crystals and inert particles may stimulate macrophages.

Exposure can continue when material is difficult to degrade or clear.

Persistent stimulation can link macrophage activation to chronic injury.

Persistent particle

Macrophage activation

Continued inflammatory response

SCHEMATIC

Slide 36 · Classically activated cells emphasize destruction

NO and ROS enhance microbial killing.

Lysosomal enzymes destroy ingested material.

Inflammatory cytokines amplify host recruitment and activation.

Reactive species

Lysosomal enzymes

Inflammatory cytokines

SCHEMATIC

Slide 37 · ROS and NO illustrate the defense–injury tradeoff

Both reactive species are part of the macrophage microbicidal arsenal.

Production helps eliminate pathogens.

Inappropriately sustained release can contribute to tissue damage.

Beneficial setting

Controlled activation

Pathogen elimination

Host protection

Pathologic setting

Excessive activation

Collateral cellular injury

Chronic tissue destruction

SCHEMATIC

Slide 38 · Classical activation can prolong inflammation

Classically activated macrophages secrete inflammatory cytokines.

Additional cell recruitment increases the number of active leukocytes.

Persistent stimulation can maintain a destructive tissue microenvironment.

Stimulus persists

M1-like mediators

Recruitment

Persistent injury

↺ Reinforcing feedback

SCHEMATIC

Slide 39 · Alternative activation is induced by IL-4 and IL-13

IL-4 and IL-13 can be released by T lymphocytes and other cells.

These signals promote an alternative macrophage program.

The pathway contrasts with IFN-γ-driven classical activation.

IL-4 / IL-13

Alternative activation

Resolution / repair

SCHEMATIC

Slide 40 · Alternatively activated macrophages promote repair

They are relatively less focused on direct microbial killing.

They help dampen or terminate inflammatory responses.

They stimulate tissue repair programs after injury.

Inflammation resolution

Repair signaling

Tissue remodeling

SCHEMATIC

Slide 41 · M1-like versus M2-like: A functional comparison

Dimension

M1-like / classical

M2-like / alternative

Typical inducer

TLR signals; IFN-γ

IL-4; IL-13

Strongest emphasis

Killing and inflammation

Resolution and repair

Characteristic outputs

NO, ROS, cytokines

Reparative mediators

Clinical tension

Microbe killing vs injury

Healing vs fibrosis

The categories summarize different stimulus–response patterns.

Neither class describes every macrophage in a real lesion.

Interpret phenotype by function and local signals, not a single absolute label.

Slide 42 · The M1–M2 dichotomy is an imperfect model

Intermediate phenotypes exist between the two textbook extremes.

There are no precise defining markers for all macrophage states.

“M1-like” and “M2-like” better convey a continuum of activation.

Inflammatory-biased

Intermediate states

Reparative-biased

SCHEMATIC

Slide 43 · Macrophage phenotypes can coexist in one lesion

Inflammatory reactions may contain several activation states at once.

A clean sequence of M1 then M2 is plausible but not usually demonstrated.

Never infer an obligatory temporal switch from a single histologic field.

Oversimplified narrative

M1 first

M2 second

One-way switch

Textbook qualification

Phenotypes may overlap

Intermediate states common

Timing is not assured

SCHEMATIC

Slide 44 · Macrophages initiate tissue repair

Phagocytosis removes dead tissue and injurious material.

Growth factors produced by activated macrophages stimulate local cell proliferation.

The same cellular response that fights injury can help rebuild tissue.

Injury and debris

Macrophage response

Growth factors

Repair-cell proliferation

SCHEMATIC

Slide 45 · Growth factors connect macrophages to regeneration

Activated macrophages are major growth-factor sources at injured sites.

Growth factors act on surviving parenchymal and stromal cells.

Regeneration also depends on tissue proliferative capacity and intact ECM.

Surviving tissue cells

Endothelial cells

Fibroblasts

Growth factors

SCHEMATIC

Slide 46 · Fibrosis is one possible outcome of sustained repair

Macrophage- and lymphocyte-derived cytokines activate fibroblasts.

Fibroblasts and myofibroblasts deposit extracellular matrix (ECM).

When tissue architecture is lost, connective tissue replaces damaged parenchyma.

Persistent injury

Macrophage cytokines

Fibroblast response

Collagen / fibrosis

SCHEMATIC

Slide 47 · TGF-β has a central fibrogenic role

Transforming growth factor-β (TGF-β) is a potent driver of fibrosis.

It helps promote ECM accumulation during repair.

In persistent injury, reparative signaling may produce excessive scarring.

Macrophage-associated repair signals

TGF-β activity

ECM deposition

Scar

SCHEMATIC

Slide 48 · Scar remodeling requires matrix turnover

Matrix metalloproteinases (MMPs) digest ECM constituents.

Macrophages are one of several cellular sources of MMPs.

Tissue inhibitors of metalloproteinases (TIMPs) restrain enzyme activity.

ECM synthesis

MMP-mediated degradation

TIMP inhibition

SCHEMATIC

Slide 49 · The injury–repair balance determines tissue outcome

Effective removal of the stimulus favors resolution.

Continuing inflammation drives ongoing damage and repair signaling.

Fibrosis becomes important when normal architecture cannot be restored.

Resolution favored

Offending agent removed

Macrophage decline

Repair completes

Fibrosis favored

Persistent injury

Continued cytokine output

Collagen accumulation

SCHEMATIC

Slide 50 · Chronic lesions combine damage and healing

Activated macrophages are a source of tissue-destructive products.

Other macrophage outputs stimulate fibroblasts and angiogenic repair.

Both effects can be present within the same chronic lesion.

Destructive products

Growth factors

Persistent macrophages

SCHEMATIC

Slide 51 · Granulomas represent organized macrophage-rich responses

Granulomatous inflammation contains collections of activated macrophages.

T lymphocytes are often present; Necrosis may occur.

Organization attempts to contain agents difficult to eradicate.

Persistent offending agent

Macrophage activation

Cellular aggregation

Granuloma

SCHEMATIC

Slide 52 · Epithelioid cells are activated macrophages

Activated macrophages may gain abundant cytoplasm.

Their appearance can resemble epithelial cells, hence “epithelioid.”

This is a morphologic response, not epithelial lineage conversion.

Ordinary macrophage

Mononuclear phagocyte

Active uptake and signaling

Epithelioid macrophage

Abundant cytoplasm

Clustered in granuloma

SCHEMATIC

Slide 53 · Multinucleated giant cells arise by macrophage fusion

Some activated macrophages fuse into multinucleate giant cells.

Giant cells may occur around foreign material or within immune granulomas.

Their presence must be interpreted within the full lesion context.

Activated macrophages

Cell fusion

Multinucleated giant cell

SCHEMATIC

Slide 54 · Foreign-body and immune granulomas differ mechanistically

Foreign-body granulomas form against material too large for phagocytosis.

Immune granulomas result from persistent T-cell-mediated responses.

Both contain macrophage-derived epithelioid cells and potentially giant cells.

Foreign-body granuloma

Inert / large material

No specific T-cell response required

Macrophages surround object

Immune granuloma

Persistent antigen

T-cell activation

Macrophage activation via cytokines

SCHEMATIC

Slide 55 · Th1–macrophage circuits can sustain granulomas

Antigen presentation and macrophage-derived cytokines stimulate T cells.

Th1-derived IFN-γ activates macrophages.

Continued interaction maintains the granulomatous response.

Antigen persistence

Macrophage presentation

Th1 / IFN-γ

Activated macrophages

↺ Reinforcing feedback

SCHEMATIC

Slide 56 · Granuloma formation is not necessarily harmless

Aggregation may help contain persistent injurious agents.

Activated macrophages also release tissue-injuring mediators.

The containment response can therefore distort or destroy tissue.

Protective aspect

Contain persistent agent

Focused cellular response

Potential cost

Local parenchymal injury

Architectural distortion / scarring

SCHEMATIC

Slide 57 · Persistent infection: A macrophage-centered example

Mycobacteria can evoke long-standing cell-mediated inflammation.

Th1 and macrophage responses may produce immune granulomas.

Morphologic recognition must prompt evaluation for an infectious cause.

Persistent microbe

T-cell / macrophage activation

Granulomatous inflammation

SCHEMATIC

Slide 58 · Silica exposure: The problem of a persistent particle

Particulate silica is an exogenous agent linked to chronic lung inflammation.

It is not readily degraded and may maintain tissue injury.

This illustrates why persistent material can sustain macrophage-rich inflammation.

Silica particles

Persistent lung stimulus

Chronic inflammatory response

SCHEMATIC

Slide 59 · Autoimmunity can perpetuate macrophage activation

Persistent immune recognition of self-antigens maintains inflammatory signaling.

Macrophages and lymphocytes can reinforce one another.

Tissue damage and later fibrosis are possible consequences.

Self-antigen response

Lymphocyte activation

Macrophage signaling

Tissue injury

↺ Reinforcing feedback

SCHEMATIC

Slide 60 · Macrophage-rich chronic lung injury: Interpreting a lesion

A chronic infiltrate should be evaluated together with parenchymal destruction.

Fibrosis indicates attempted repair and loss of architecture.

These findings form a pathologic pattern; They do not alone establish etiology.

Inflammatory cells

Destroyed alveolar structures

Fibrosis

SCHEMATIC

Slide 61 · Distinguish a chronic infiltrate from acute exudation

Acute inflammation typically emphasizes neutrophils, vascular changes and edema.

Chronic inflammation emphasizes mononuclear cells, damage and repair.

Mixed acute and chronic patterns occur, especially with repeated injury.

Acute pattern

Neutrophil-rich exudate

Edema / vascular change

Chronic pattern

Macrophages + lymphocytes

Tissue loss + fibrosis

SCHEMATIC

Slide 62 · Application: Persistent antigen and a T-cell loop

A lesion remains inflamed despite an extended host response.

Macrophages present antigen; T cells release IFN-γ.

Interpretation: Reciprocal activation can explain persistent macrophage activity.

Macrophage antigen display

Th1 activation

IFN-γ

Classical macrophage activation

↺ Reinforcing feedback

SCHEMATIC

Slide 63 · Application: Healing response becomes scarring

An injurious agent persists while macrophages remain activated.

Fibroblast stimulation and ECM deposition continue alongside injury.

Interpretation: Repair signaling may become pathologic fibrosis.

Persistent damage

Macrophage signals

Fibroblast activation

Fibrosis

SCHEMATIC

Slide 64 · Application: Interpret macrophage activation labels

A macrophage-rich lesion expresses inflammatory and reparative programs.

M1/M2 are useful functional shorthand but do not define rigid populations.

Interpretation: Macrophage states may be mixed and dynamic.

Local stimuli

Diverse macrophage states

Mixed functional outputs

SCHEMATIC

Slide 65 · Integrating macrophages into chronic inflammation

Origins and recruitment set the cells available within a lesion.

Activation signals determine inflammatory, microbicidal and reparative outputs.

Outcome reflects stimulus persistence, T-cell interactions and tissue response.

Origin + recruitment

Activation

Defense + injury + repair

Outcome

SCHEMATIC

Slide 66 · Final synthesis: Four mechanistic principles

Macrophages can be long-lived tissue residents or recruited monocyte descendants.

Activated cells destroy microbes and also risk collateral tissue damage.

Interactions with T lymphocytes help sustain chronic inflammation.

Macrophages coordinate repair; Persistent activation can lead to fibrosis.

Defense

Chronic injury

Repair / fibrosis

SCHEMATIC

Slide 67 · Reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026)

Inflammation and Repair