Cells and Mediators of Chronic Inflammation

Slide 1 · Cells and Mediators of Chronic Inflammation

Cellular circuits linking persistent injury, host defense, and tissue repair

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Identify the principal cellular populations in chronic inflammation.

Explain macrophage recruitment, activation, and functional consequences.

Connect T-cell cytokines to macrophage and granulocyte responses.

Interpret how persistent inflammation produces injury and fibrosis.

Slide 3 · The chronic inflammatory response has three linked components

Mononuclear infiltrate

Macrophages, lymphocytes, plasma cells

Tissue injury

Persistent agent and activated leukocytes

Repair response

Angiogenesis and fibrosis

Cellular activation produces mediators that connect all three components.

Their proportions vary with the stimulus and stage of disease.

Slide 4 · Persistence drives continuing cellular activation

Persistent stimulus

Microbe, immune reaction, toxic material

Ongoing recruitment

Monocytes and lymphocytes enter tissue

Mediator release

Leukocyte activation is sustained

Damage and repair

Destruction coexists with fibrosis

A stimulus that cannot be cleared maintains the local inflammatory circuit.

Slide 5 · Acute and chronic inflammation differ in their dominant pattern

Acute inflammation

Chronic inflammation

Vascular dilation and exudation prominent

Edema and neutrophils often predominate

Often resolves when stimulus clears

Mononuclear leukocyte infiltrates

Tissue destruction by agents and cells

Angiogenesis and fibrosis may coexist

Slide 6 · Three etiologic settings commonly initiate chronic inflammation

Persistent infection

Mycobacteria; Selected viruses, fungi, and parasites

Immune dysregulation

Autoimmunity, allergic responses, inappropriate responses to microbes

Prolonged toxic exposure

Silica particles or endogenous lipid accumulation

These are representative categories, not an exhaustive classification.

Slide 7 · Many cell types act through overlapping mediator networks

Chronic inflammatory focus

Macrophages

TNF, IL-1, chemokines

CD4 T cells

IFN-γ; IL-4, IL-13; IL-17

Plasma cells

Antibodies

Other leukocytes

Eosinophils, mast cells, neutrophils

The integrated response—not any single cytokine—determines injury and repair.

Slide 8 · Macrophages usually dominate the cellular response

Professional phagocytes remove microbes and damaged tissue.

Activated macrophages secrete inflammatory cytokines and growth factors.

They present antigen and communicate with T lymphocytes.

They can both damage tissue and initiate repair.

Slide 9 · Macrophages have three complementary effector roles

Elimination

Phagocytosis and destruction of microbes or dead cells

Inflammatory coordination

Cytokines and lipid mediators propagate leukocyte responses

Repair and remodeling

Signals promote healing, scarring, and fibrosis

Slide 10 · Inflammatory macrophages commonly derive from blood monocytes

Bone marrow

Hematopoietic progenitors

Blood

Circulating monocytes

Tissue entry

Adhesion and chemotaxis

Inflammatory site

Differentiated macrophages

The same general trafficking machinery recruits neutrophils and monocytes.

Slide 11 · Some resident macrophages have embryonic origins

Macrophage ontogeny

Postnatal marrow

Blood monocytes

Inflammatory macrophages

Yolk sac / fetal liver

Embryonic tissue seeding

Stable resident populations

Slide 12 · Monocytes and tissue macrophages have different residence times

Circulating monocytes

Blood half-life ~1 day

Recruitment into inflammation

Monocytes can predominate within 48 hours

Tissue macrophages

Survival may extend for months or years

These are typical values from the text, not universal lifespans.

Slide 13 · Resident and recruited populations coexist

Resident macrophages

Monocyte-derived macrophages

Often seeded early in development

Maintain stable local populations

Examples: Microglia, Kupffer cells, alveolar macrophages

Arise from postnatal marrow progenitors

Accumulate after blood recruitment

Prominent at inflammatory sites; Also in some normal tissues

Slide 14 · Organ-specific macrophages share a phagocyte lineage

Site

Resident phagocyte

Practical association

Brain

Microglia

Local immune surveillance

Liver

Kupffer cells

Liver macrophages

Lung

Alveolar macrophages

Alveolar clearance

Spleen / lymph node

Sinus histiocytes

Sinus-associated phagocytes

Slide 15 · Mononuclear phagocyte system is the preferred collective term

Includes monocytes and diverse tissue macrophage populations.

Macrophages are found diffusely in connective tissue and in specialized organ locations.

“Reticuloendothelial system” is a historical and inaccurate synonym.

Slide 16 · Monocyte recruitment relies on adhesion and chemotaxis

Endothelial interaction

Adhesion molecules

Transvascular migration

Movement out of blood

Tissue navigation

Chemotactic cues

Macrophage accumulation

Local differentiation

Recruitment continues while the inflammatory stimulus persists.

Slide 17 · Phagocytosis supports clearance of persistent stimuli

Recognition

Microbe or damaged tissue

Engulfment

Phagocytic uptake

Killing / digestion

Intracellular effector machinery

Clearance

Removal of injurious material

Persistent or resistant agents may prevent complete resolution.

Slide 18 · Macrophages produce key inflammatory mediators

Mediator

Source role

Main effect here

TNF

Activated macrophages

Promotes inflammation and cell recruitment

IL-1

Activated macrophages

Amplifies inflammatory signaling

Chemokines

Activated leukocytes

Direct migration of other leukocytes

Eicosanoids

Activated macrophages

Contribute to inflammatory responses

Slide 19 · Growth and repair signals link inflammation with fibrosis

Activated macrophages

Repair-associated mediators

Local stromal response

Fibroblasts and tissue remodeling

Connective-tissue deposition

Scar / fibrosis

Macrophages participate in tissue repair as well as tissue destruction.

Slide 20 · Macrophage activation can protect and injure the host

Protective functions

Potential costs

Kill ingested microbes

Remove necrotic material

Organize defense with T cells

Oxidants and enzymes may injure host tissue

Cytokines sustain destructive inflammation

Excessive repair can produce fibrosis

Slide 21 · Antigen presentation places macrophages in adaptive immunity

Macrophage

Processes and displays antigen

T lymphocyte

Recognizes antigen + costimulation

T-cell activation

Cytokine production

Macrophage response

Further activation

Reciprocal signaling creates a self-reinforcing response.

Slide 22 · Macrophage activation has two illustrative poles

Classical activation (M1-like)

Alternative activation (M2-like)

Microbial signals; IFN-γ

Microbicidal effectors and inflammation

ROS, NO, lysosomal enzymes

IL-4 and IL-13

Resolution-associated and reparative responses

Tissue repair and remodeling

Slide 23 · Classical activation begins with microbial and immune signals

Microbial molecules

Engage Toll-like receptors and other sensors

IFN-γ

Produced by T lymphocytes during immune responses

Particulates / crystals

Foreign substances can stimulate macrophage activation

Slide 24 · Classical activation increases antimicrobial capacity

Classical signals

Microbes or IFN-γ

Macrophage response

NO + ROS + lysosomal enzymes

Functional effects

Kill ingested organisms; Stimulate inflammation

The same effector products can damage neighboring host tissue.

Slide 25 · Reactive effector products contribute to chronic tissue injury

Reactive oxygen species

Help kill microbes but can injure host cells

Nitric oxide

Participates in microbicidal effector function

Lysosomal enzymes

Digest targets but can damage surrounding tissue

Slide 26 · Alternative activation is favored by IL-4 and IL-13

Th2 and other cells

IL-4; IL-13

Alternative activation

M2-like macrophage response

Functional emphasis

Repair and termination of inflammation

Alternative activation is not primarily a microbicidal program.

Slide 27 · M2-like responses support repair rather than microbicidal killing

Inflammatory emphasis

Reparative emphasis

Eliminate microbes and debris

Inflammatory cytokines propagate the reaction

Collateral tissue destruction possible

Down-regulate inflammatory response

Support tissue repair

Excessive repair may culminate in scar formation

Slide 28 · M1 and M2 are conceptual endpoints, not rigid cell classes

Intermediate macrophage states may not fit either label.

Defining markers for these subsets are imprecise.

Different macrophage phenotypes often coexist within one lesion.

The terms “M1-like” and “M2-like” reflect this limitation.

Slide 29 · A universal M1-to-M2 sequence is not established

Conceptual model

Inflammation precedes repair

Observed heterogeneity

Activation programs overlap

Interpretive caution

No fixed sequence demonstrated in most lesions

Do not infer macrophage phenotype solely from lesion age.

Slide 30 · Macrophage accumulation can persist by two processes

Persistence of macrophages

Continued recruitment

Monocytes enter from blood

Ongoing stimulus sustains entry

Local proliferation

Resident or recruited cells divide

Tissue population remains expanded

Slide 31 · Removal of the stimulus permits macrophage clearance

Offending agent removed

Stimulus declines

Macrophage persistence wanes

Death and/or lymphatic exit

Inflammation subsides

Repair and resolution become possible

Failure to remove an agent allows accumulation and injury to continue.

Slide 32 · Lymphocytes can amplify and prolong inflammation

Persistent microbes and environmental antigens activate T and B lymphocytes.

Memory lymphocytes contribute to long-lived responses.

Lymphocytes may dominate infiltrates in autoimmune diseases.

Activated T cells determine the pattern of leukocyte recruitment.

Slide 33 · Immunologic memory can sustain a chronic tissue reaction

Ongoing antigen exposure

Persistent microbe or self-antigen

Lymphocyte activation

Effector and memory responses

Repeated mediator release

Chronic tissue inflammation

The source associates persistent severe reactions with long-lived immune memory.

Slide 34 · CD4 T-cell subsets create distinct cytokine programs

T-cell subset

Principal cytokines

Characteristic downstream response

Th1

IFN-γ

Classical macrophage activation

Th2

IL-4, IL-13; IL-5

Alternative macrophage activation; Eosinophils

Th17

IL-17 and others

Chemokines; Neutrophil and monocyte recruitment

Slide 35 · Th1-derived IFN-γ drives classical macrophage activation

Antigen-stimulated Th1 cell

Releases IFN-γ

Macrophage

Classical activation

Tissue effect

Antimicrobial activity and inflammation

Th1–macrophage interactions are central to many persistent cellular immune responses.

Slide 36 · Th2 cells coordinate eosinophils and alternative activation

Activated Th2 lymphocyte

IL-5

Eosinophil recruitment and activation

Helminths / allergy

IL-4 and IL-13

IgE response and M2-like activation

Repair-associated response

Slide 37 · Th17 cytokines support ongoing granulocyte recruitment

Activated Th17 cell

IL-17 and other cytokines

Chemokine production

Cells in inflamed tissue respond

Leukocyte entry

Neutrophils and monocytes

Th17 activity helps explain neutrophils in some chronic lesions.

Slide 38 · T-cell programs vary with the offending stimulus

Th1 / Th17 emphasis

Th2 emphasis

Defense against many microbes

Can contribute to autoimmune tissue injury

Macrophage activation or neutrophil recruitment

Responses to helminth parasites

Allergic inflammatory conditions

IgE, eosinophils, alternative macrophage activation

Slide 39 · Cytokine effects depend on cellular source and target

Signal

Typical cellular source

Relevant target or consequence

IFN-γ

Th1 cells

Classical macrophage activation

IL-4 / IL-13

Th2 cells

Alternative activation; IgE response

IL-5

Th2 cells

Eosinophil recruitment / activation

IL-17

Th17 cells

Chemokine-mediated cell recruitment

IL-12

Macrophages

T-cell stimulation

Slide 40 · Macrophages activate T cells through multiple inputs

Antigen presentation

Processed antigen displayed to T cells

Costimulation

Macrophage membrane molecules provide signals

Cytokine output

IL-12 and other mediators stimulate T cells

Slide 41 · Activated T cells recruit and stimulate macrophages

Activated T lymphocyte

Cytokine-producing cell

IFN-γ

Activates macrophages

TNF / chemokines

Facilitate recruitment

Persistent response

More antigen presentation

Recruitment and activation are related but distinct cytokine effects.

Slide 42 · Macrophage–T-cell feedback sustains chronic inflammation

Macrophage

Antigen + IL-12

T lymphocyte

Activation and cytokines

Monocyte recruitment

TNF and chemokines

Macrophage pool

Activation and presentation

Reinforcing signals can continue while antigen persists.

Slide 43 · Recruitment and activation should be distinguished

Recruiting cells

Activating effector cells

TNF, chemokines and IL-17-associated signals

Increase leukocyte accumulation at tissue site

Changes the number and composition of cells

IFN-γ activates macrophages

IL-4 / IL-13 favor alternative activation

Changes functional state of existing cells

Slide 44 · Sustained T-cell–macrophage reactions may form granulomas

Persistent antigen

Difficult to eradicate

T-cell–macrophage circuit

Repeated activation

Macrophage aggregation

Epithelioid transformation possible

Granulomatous response

Localized containment attempt

Granulomatous inflammation is a separate specialized chronic inflammatory pattern.

Slide 45 · Activated B cells and plasma cells are common participants

Plasma cells are terminally differentiated antibody-secreting B cells.

Antibodies may bind persistent microbial, self, or altered tissue antigens.

B-cell and plasma-cell infiltrates often accompany T cells and macrophages.

Slide 46 · Antibody detection does not establish pathogenic contribution

Antibodies may be directed against persistent foreign antigens.

Others may recognize self-antigens or altered tissue components.

The contribution of antibodies to many chronic inflammatory disorders remains unclear.

Interpret plasma-cell infiltration within the etiologic and tissue context.

Slide 47 · Some lesions develop organized tertiary lymphoid structures

Chronic cellular infiltrate

Lymphocytes + antigen-presenting cells

Local organization

Follicle-like aggregates with plasma cells

Tertiary lymphoid structure

Resembles a lymph node follicle

Reported in rheumatoid synovium, Hashimoto thyroiditis, and some tumors.

Slide 48 · Tertiary lymphoid structures are context-dependent findings

Established observation

Unresolved interpretation

Organized follicles can form at non-lymphoid inflammatory sites

T cells, B cells, and antigen-presenting cells colocalize

Identifiable in some chronic lesions

Local follicles may perpetuate immune reactions

The source does not establish their causal importance

Presence alone does not prove a specific mechanism

Slide 49 · Other inflammatory cells reflect the dominant stimulus

Cell population

Common setting

Key mediator or action

Eosinophils

Th2 reactions, helminths, allergy

Major basic protein

Mast cells

Immediate hypersensitivity; Chronic lesions

IgE/FcεRI and cytokines

Neutrophils

Persistent infection or irritants

Continued recruitment and injury

Slide 50 · Eosinophil recruitment is prominent in Th2-type reactions

Th2-associated stimulus

Helminths or some allergies

Chemotaxis

Eotaxin and adhesion signals

Eosinophil accumulation

Granulocyte-rich inflammatory foci

Eotaxin can arise from leukocytes and epithelial cells.

Slide 51 · Eosinophil major basic protein is protective and injurious

Host defense

Collateral injury

Granule protein is toxic to helminths

Useful in responses to some parasites

Major basic protein can injure host epithelium

Contributes to damage in allergic disorders

Slide 52 · Mast cells participate in both acute and chronic inflammation

Mast cells are widely distributed in connective tissue.

They express high-affinity FcεRI receptors that bind IgE.

Antigen recognition through bound IgE can trigger degranulation.

Mast-cell cytokines can contribute to chronic inflammation.

Slide 53 · Mast-cell activation links antigen recognition to mediators

Mast-cell FcεRI

Binds IgE

Antigen recognition

Engages surface-bound IgE

Degranulation

Histamine and lipid mediators

Tissue response

Allergic inflammation

Immediate allergic activation is distinct from the broader chronic cytokine contribution.

Slide 54 · Mast-cell cytokines can maintain inflammation

Immediate response

Histamine and prostaglandins after IgE-dependent activation

Chronic role

Multiple cytokines can promote inflammatory responses

Interpretation

Mast cells are not restricted to acute hypersensitivity

Slide 55 · Neutrophils are not exclusive to acute inflammation

Chronic inflammatory lesions may continue to contain neutrophils.

Persistent microbes can maintain their recruitment.

Activated macrophages and T cells supply recruiting signals.

Mixed acute and chronic inflammation is therefore compatible with a chronic process.

Slide 56 · Chronic osteomyelitis can maintain neutrophilic exudates

Clinical / morphologic scenario

A bone lesion has persisted for months. Histology shows ongoing neutrophilic exudate together with chronic tissue injury.

Does a neutrophilic infiltrate alone exclude chronic inflammation?

Interpretation

No. Persistent bacterial infection can sustain neutrophils during chronic osteomyelitis.

Slide 57 · Irritant exposure may sustain chronic neutrophilic injury

Repeated inhaled irritants

Smoking or similar stimulus

Inflammatory signaling

Continued leukocyte recruitment

Neutrophil response

Contributes to lung injury

Smoking-associated chronic lung injury.

Slide 58 · A mixed inflammatory infiltrate needs etiologic interpretation

Cellular clues

Interpretive requirement

Neutrophils suggest ongoing active recruitment

Macrophages and lymphocytes suggest chronic response

Eosinophils suggest some Th2-type settings

Identify persistent infection, immune reaction, or toxin

Assess tissue destruction and fibrosis

Avoid diagnosing etiology from one cell type alone

Slide 59 · A chronic lesion is simultaneously destructive and reparative

Schematic tissue response (not a histologic specimen)

Mononuclear infiltration

Macrophages / lymphocytes

Parenchymal destruction

Tissue loss

Fibrous replacement

Connective tissue

Slide 60 · Clinical example: Rheumatoid synovium

Clinical / morphologic scenario

A chronically inflamed synovium contains macrophages, lymphocytes, plasma cells, and follicle-like lymphoid aggregates.

Which two processes can sustain the lesion?

Interpretation

Persistent adaptive immune activation and reciprocal macrophage–lymphocyte signaling; Organized follicles may coexist.

Slide 61 · Clinical example: Allergic or helminth-associated inflammation

Clinical / morphologic scenario

An inflammatory focus contains numerous eosinophils and activated lymphocytes.

Which T-helper program and damaging effector are consistent with this pattern?

Interpretation

Th2 responses (including IL-5); Eosinophil major basic protein may injure host epithelium.

Slide 62 · Clinical example: Sustained macrophage activation

Clinical / morphologic scenario

A persistent pathogen stimulates T cells and macrophages. IFN-γ activity is prominent and local tissue damage progresses.

Which macrophage pathway and consequence are expected?

Interpretation

Classical (M1-like) activation with antimicrobial ROS/NO/enzyme activity and possible host-tissue injury.

Slide 63 · Match mediators to the cellular processes they regulate

Process

Representative mediator(s)

Tissue consequence

Macrophage activation

IFN-γ

Microbicidal activity; Potential damage

Alternative activation

IL-4 and IL-13

Repair-oriented responses

Eosinophil response

IL-5; Eotaxin

Helminth defense; Epithelial injury

Leukocyte recruitment

Chemokines; IL-17-associated signals

Persistent cellular infiltration

Local amplification

TNF, IL-1

Sustained inflammatory responses

Slide 64 · The central mechanism is a self-sustaining cellular circuit

Persistent stimulus

Microbe / antigen / toxin

Activated lymphocytes

Subset-specific cytokines

Activated macrophages

Mediators and antigen presentation

Tissue reaction

Injury, recruitment, fibrosis

Breaking stimulus persistence changes the circuit; Otherwise repair may coexist with continuing damage.

Slide 65 · Synthesis: Interpret cells, mediators, and tissue consequences together

Macrophages coordinate phagocytosis, inflammation, and repair.

Th1, Th2, and Th17 programs produce different cellular patterns.

B cells, eosinophils, mast cells, and neutrophils modify the reaction.

Persistent activation explains simultaneous tissue destruction and fibrosis.

Slide 66 · Reference and source scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. Chapter 3: Inflammation and Repair.

Sections: Chronic Inflammation; Cells and Mediators of Chronic Inflammation; Role of Macrophages; Role of Lymphocytes; Other Cells in Chronic Inflammation.

Original explanatory schematics are constructed from the supplied textbook excerpt; they are not reproduced textbook figures.