Lecture 9: Acute Inflammation - cytokines & cells Flashcards
What are cytokines
small molecules released from inflammatory cells to control inflammation
What are chemokines
chemotactic cytokines - “find me” signals to recruit immune cells
What did William Coley show?
He showed that the activation of immune system (in response to bacterial infections) can allow immune cells to target cancers.
- forerunner of today’s immunotherapies, mixed efficacy.
Examples of cytokines:
TNF (tumor necrosis factor, IL (Interleukins), IFN (Interferons)
What are the effects of acute inflammation with low levels of TNF?
Vasodilation, vasopermeability, inflammatory cells activated, expression of endothelial adhesion molecules (i.e. ICAM-1, selectins P and E, VCAM-1)
What are the chronic effects of TNF?
Fever, production of scars, cachexia (muscle atrophy), activated coagulation system
Process of mobilisation of inflammatory cells?
Attraction to sites of injury > neutrophil recruitment > adhesion to endothelial cells > transmigration to tissues (diapedesis) > chemotaxis to sites of injury.
1) Attraction to site of injury/damage
In sterile inflammation (injury based), injured cells release DAMPs > PRR of macrophages and neutrophils. Triggers intracellular signalling cascades.
Cytokines IL-1a and IL-1b are secreted to signal endothelial cells to allow for vasopermeability.
Cytokines IL-1a and IL-1b function
Cytokines IL-1a and IL-1b are secreted by macrophages and neutrophils to signal endothelial cells to allow for vasopermeability.
They bind to endothelial cells and activate the expression of P then E selectins (adhesion molecules).
2) Margination and adhesion
Increased vasopermeability leads to loss of plasma (into interstitial space), increased blood viscosity. Alters blood flow.
Neutrophils move from central axial location towards plasmatic zone (margination) - towards edges of endothelial cells. The P and E-selectins cause the neutrophils to slow down, roll, then stop through interaction w/ glycoproteins in neutrophils.
Firm adhesion is between ICAM1 and VCAM1 on endothelial cells, and LFA1 (leukocyte functioning antigen) on neutrophils
3) Transmigration (diapedesis)
Adhesion to endothelial cells stimulates secretion of Elastase - digest basement membrane.
Neutrophils and other BC move between endothelial cells.
4) Chemotaxis and Necrotaxis
Chemotaxis - moving towards site of inflammation in interstitial space - due to infection
Necrotaxis - moving towards site of inflammation in interstitial space - due to injury
Chemotactic signals during chemotaxis and necrotaxis
Mitochondrial or bacterial N-formulated peptides, chemokines, C3a & C5a, bradykinin, LTB4, IL-8 (to recruit more immune cells)
5) Function of neutrophils and macrophages: opsonisation?
Tagging of damaged cell/bacteria with immunoglobulins and C3b.
5) Function of neutrophils and macrophages: adhesion
Phagocytes bind to opsonins (molecular tag on cell/bacteria) by specific surface receptors
5) Function of neutrophils and macrophages: phagocytosis
pseudopodia extend around particle and internalise them into membrane bound particles (phagosomes)
5) Function of neutrophils and macrophages: degranulation
Fusion of Phagosomes with with acidic lysosomes, containing proteases (i.e. cathepsin G, elastase, proteinase 3). Removes visible lysosomes from cytoplasm.
Elastase
Enzyme used to break basement membrane of blood vessel, and digests phagosome (when phagosome and lysosome fuse).
5) Function of neutrophils and macrophages: Respiratory burst/activation of lysosomal proteases
- On the surface of phagolysosome, an ETC complex - NOX2 (NADPH oxidase) forms.
- O2 is reduced to superoxide, which induces K+ influx which releases proteases from their repressive carriers.
- SOD activity reduces superoxide to peroxide and forms hydrogen peroxide which raises pH to 9.0.
- This activates enzymes and proteolysis of the contents of the phagolysosome.
6) After effects of phagocytosis
- Removal through protein degradation in phagolysosome.
- potential damage to host cell if enzymes leak into intracellular structure.
- if particle is too large to be engulfed, cell releases cytotoxic agents (cause collateral damage).
- Macrophage can become antigen presenting cells.
Systemic inflammation
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