inflammation

• Traditional signs of inflammation

  • Redness
  • Swelling
  • Pain
  • Heat
  • Destruction of tissue/function
• Inflammation


  An innate immune response, which occurs after injury or breach of the epithelial barriers to defend against micro-organisms and promote tissue repair
• Stages of inflammation

  1. PRRs on the surface of cells near to the infection site sense damage associated molecular patterns

  2. Inflammatory cells such as neutrophils and macrophages are attracted to the site of infection through chemokines

  3. PRRs on the surface of host cells, binds to LPS and through signal transduction initiates a signal cascade which upregulates transcription of genes involved in pro-inflammatory cytokine production

  4. This recruits additional immune cells to the site of inflammation and infection, in order to phagocytose damaged cells
• Neutrophil Recruitment

  1. Leukocytes become tethered to the endothelial cells of the bloodstream

  2. B2 integrins like LFA-1 interact with ICAM-1 on endothelial cells promote tight adhesion of the neutrophil to the blood vessel wall

  3. The neutrophil can transmigrate by diapedesis across the endothelial barrier, from the blood vessels into tissue
• Paracellular transendothelial migration


  Leukocytes move between adjacent endothelial cells by passing through tight or adheren junctions between them
• Transcellular transendothelial migration


  Leukocyte directly penetrates through the body of an endothelial cell by creating pores within the cell through invasive podosomes
• Inflammasomes


  1. A cytoplasmic, endosome-bound PRR senses DAMPs or PAMPs

  2. Signal transduction/signal cascade: activate transcription factors like AP-1, induce expression of pro inflammatory cytokines like IL-18 and inflammasome components

  3. Assembly of inflammasome complex: sensor protein, adaptor protein and pro-caspace-1

  4. ACTIVATION of caspase 1, cleaves pro inflammatory cytokines into their active form

  5. Caspase 1 induces pyroptosis – cell death through membrane rupture and cell swelling
• Resolution of Inflammation

  1. Efferocytosis: when macrophages phagocyte apoptotic cells, this initiates the release of anti-inflammatory cytokines such as IL-10 and TNF-B from the macrophage to resolve inflammation

  2. This causes the macrophage to develop into the M2 macrophage phenotype, promoting wound healing
• Failure to resolve inflammation can result in a range of inflammatory diseases, such as inflammatory bowel syndrome and arthritis
• Gout

  • A form of arthritis, which causes pain in joints and surrounding tissues
  • Due to elevated levels or uric acid in the bloodstream, which is usually filtered by the kidney into urine, uric acid crystals can form in the body
  • Elevated levels or uric acid may be due to kidney dysfunction, diet, obesity, or diuretic medications
  • Uric acid is more likely to crystallise in the colder extremities of the body, such as the toes
  • When phagocytes attempt to clear the debris, uric acid crystals damage lysosomes which triggers the activation of the NLRP3 inflammasome complex, which releases inflammatory cytokines such as IL-1B
• Treatments for Gout


  • Inflammatory cytokine inhibitors like canakinumab, which is a monoclonal antibody that binds to IL-1B preventing it from binding to cellular receptors
  • Small molecular inhibitors can bind to IL-1B Receptors
  • Use of soluble decoy receptors such as rilonacept/anakinra can bind to IL-1B
• Inflammatory mediators are released by cells at the site of injury or infection, leading to vasodilation (increased blood flow) and increased permeability of capillaries.
• The release of histamine from mast cells causes vasodilation and increases vascular permeability.
• Histamine also stimulates nerve endings that cause pain.