L3: Molecular and Cellular Mechanism of Inflammation

Learning Objectives

• Define inflammation

• Distinguish between acute and chronic inflammation

• Understand the role of cytokines and chemokines in inflammation

• Dual roles of cytokines as pro- and anti-inflammatory mediators

• Understand the cellular mechanisms of inflammation

• Chronic inflammation in autoimmune diseases

Definitions

• body’s attemption of removing harmful stimuli and starting the healing process

• types of stimuli causing vascularised tissue damage

  • pathogens

  • noxious stimuli

    • chemicals

    • stings

  • physicla injury

  • hypersensitivity and autoimmune disease

• Types of inflammation (chronic)

  • metabolic syndrome

  • arthritis

  • alzheimer’s disease

  • asthma

  • ulcerative colitis and inflammatory Bowel disease

  • colon, breasy and lung cancers

  • eye disorders

  • cardiovascular disease

  • gingivitis

• symptoms fo acute inflammation

  • heat: increased blood flow to affected area

  • redness: capillaries filled with blood

  • swelling: increased permeability of blood vessels → buildup of fluid and exudation of plasma proteins

  • pain: increased bradykinin release → stimulate nerve endings

    • ★internal organ inflammation: not many nerve endings → no pain

  • immobility: loss of function

Process of Inflammation

Recognition of injurious agent

• infectious inflammation

  • signals: PAMPs

  • extrinsic source

  • recognised by TLRs (Toll-like receptors) on cell surface of pathogen or infected cell

  • ligands recognised (bacterial products)

    • LPS (in Gram-ve bacteria)

    • LTA (in Gram+ve bacteria)

    • flagellin

• Sterile inflammation

  • signals: DAMPs

  • endogenous source

  • recognised by NOD receptors (nucleotide oligomerisation domain) in cytosol

  • ligands recognised (released by damaged cells)

    • heat shock proteins

    • uric acid crystal

    • defensins

    • HMGB1

Recruitment of leukocytes

• Blood vessel dilation → increased blood flow

• margination: getting close to blood vessel wall

• rolling

  • binding of selectin ligand (on neutrophil) to E- or P-selectin (on endothelium)

  • binding of chemokine receptor (on neutrophil) to chemokine (IL-1 secreted by macrophage) presented by proteoglycan (on endothelium) → activate neutrophil

• adhesion: binding of β2 integrin (on neutrophil) to ICAM-1

• diapedesis (facilitated by CD31): endothelial cells contract → increase permeability → transmigrate from blood vessel to tissue

• Chemotaxis: cytokines produced by Langerhan cells and macrophage attract neutrophils to site of infection

Removal of causative regents —— Phagocytosis

• recognition and attachment: microbes bind to phagocyte receptors

• engulfment: engulf pathogens or apoptotic cells by zipping up aroound it

  • depend on polymerisation of actin filaments → plasma membrane remodelling

• fusion of phagosome with lysosome b: form phagosome → fuse with lysosome → phagolysosome

• killing and degradation: digested by lysozyme and released as exocytic vesicles

  • mediated by ROS nitric acid and lysosomal enzymes

• ★ Neutrophil extracellular traps (NETs)

  • produced by neutrophils and inflammatory mediators

  • ✔︎ chromatin materials + antimicrobial peptides and enzymes

  • trap miceobes to prevent spreading

Termination/ Resolution

• depletion of chemokines

• neutrophils apoptosis

  • induced by ROS, AncA1 and lactoferrin

• clearance of apoptotic neutrophils by macrophages

• macrophage phenotype switch: fomr pro-inflammatory → resolution-phase

Inflammatory mediators

Cytokines

• Role

  • key modulators

  • regulators of inflammation

  • chemical messengers

• types

  • interleukin

  • tumor nercrosis factors

  • interferons

  • chemokines

• produced by immune cells and non-immune cells → bind to cell surface receptors

• initiate autocrine, paracrine and endocrine effects

• functions

  • T-cell proliferation: IL-2, IL-4, IL-15, IL-21

  • Pro-inflammatory: TNF-α, IL-1, IL-6, IFN-γ

  • Anti-inflammatory: IL-10, TGF-β1, IL-6

Chemokines

• family of small cytokines

• chemotaxis: secreted by cells primary to recruit leukocyes (macrohages and monocytes) of infection or injury

• chemoattractants: adhesion molecules

• induce integrin expression: β2-integrin on lymphocytes for attachment

Hyaluronan (HA)

• large non-fulfated glycosaminoglycan in extracellular matrix

• synthesied by 3 HA synthases (HAS I, II, III) on plasma membrane → secreted to extracellular space

  • HMW HA: synthesised by HAS I and II

  • LMW HA: synthesised by HAS III

• bind to CD44

• functions

  • 

Acute and Chronic Inflammation

inducing agent

• acute

  • pathogen

  • injured tissues

  • allergens

• chronic

  • non-degradable pathogens

  • persistant foreign body

  • autoinmmune response

cells involved

• acute

  • neutrophils

  • monocytes

  • macrophage

  • basophils

  • eosinophils

  • mast cells

• chronic

  • monocytes

  • macrophage

  • lymphocytes

  • plasma cells

  • fibroblast

process

• acute

  • vacular changes

  • neutrophils recruitment

• chronic

  • angiogenesis

  • mononuclear cell infiltration

outcomes

• acute

  • resolution

  • abcess formation

  • chronic inflammation

• chronic

  • tissue destruction

  • fibrosis

  • necrosis

Chronic inflammation in autoimmune diseases

Inflammation and cell senescence

• cell senescence= early ageging of cell

• increased inflammatory mediators expression

  • TNF-α

  • IL-6

  • IL-1β

• caused by age-related frailty or chemical injury

Systemic Lupus Erythematosus (SLE)

• Type II hypersensitivity

• breakdown of self-tolerance → immune-mediated tissue damage

• causes

  • genetic factors

  • environmental factors

    • smoking

    • UV exposure (drive apoptosis)

    • microbiome or viruses (EBV)

• involved immune cells

  • autoreactivity of T cells

  • B cells

  • increased cytokines secretion

    • IFN-γ: accelerate disease

    • IL-6: promote terminal B cell differentiation

    • IL-8 and MCP-1: increase inflammatory cell recruitment

• damaged organs

  • kidney—— lupus nephritis

    • pathogenesis

      • acute stage: nephrons damged by B and T cells (treated by immunosuppressive agents)

      • chronic stage: tubular atrophy and fibrosis (chronic renal impariment → dialysis)

    • mechanism

      • indirect binding: chromatin released from dead cells are entrapped in GBM (glomerulus basal membrane) → ‘bridge’ to mediate anti-dsDNA antibody binding → glomerulonephiritis

      • direct binding: antibody bind to cell surface or extracellular matrix antigen in nephron

  • skin

  • lungs

  • brain

  • heart