Biochemical Markers in the inflammatory response

1. Biochemical Markers in the inflammatory response Dr Claire Bethune Consultant Immunologist Derriford Hospital

2. Role of the inflammatory response • Killing of invading micro-organisms • Macrophage activation, recruitment of effectors • Barrier to the spread of infection • Microvascular coagulation • Repair of injured tissue

4. The inflammatory response • Recognition of “insult” initiation of the inflammatory response • Amplification of the local response • Induce vascular permeability • Change adhesive properties of endothelium to attract more phagocytes • Activate incoming phagocytes • Activate NK cells enhancing cytotoxicity and inducing further cytokine production • Systemic involvement • Attenuation and resolution

5. Local inflammatory response – the main players • Macrophages, mast cells and dendritic cells • Recognition of infection • Cytokines, Lipid mediators of inflammation • Complement • Interferons • Kinin system • Coagulation cascade

6. Pathogen recognition • Macrophage receptors • Mannose receptors – stimulate phagocytosis • Toll-like receptors and NOD1 +2 – stimulate cytokine production, expression of co stimulatory molecules • Mannose binding lectin • Complement activation • Blood vessel injury triggers enzyme cascades • Kinin system activation • Coagulation system activation

7. Figure 2-5 Pathogen recognition by macrophages resulting in initiation of the inflammatory response

8. Toll-like receptors • Macrophages and mast cells. • Recognition of microbial components by Toll-like receptor • Leads to synthesis and secretion of proinflammatory cytokines and lipid mediators • Recruitment of soluble immune components and immune cells from the blood.

9. Figure 2-39

10. Arachidonic acid-derived lipid mediators

11. Local inflammatory response – the main players • Macrophages, mast cells and dendritic cells • Recognition of infection • Cytokines, Lipid mediators of inflammation • Complement • Interferons • Kinin system • Coagulation cascade

12. Figure 2-18 The Complement Cascade

13. Figure 2-19 Main components of the Complement Cascade

14. Local inflammatory response – the main players • Macrophages, mast cells and dendritic cells • Recognition of infection • Cytokines, Lipid mediators of inflammation • Complement • Interferons • Kinin system • Coagulation cascade

15. Interferons • IFN-α and IFN-β produced by host cells in response to viral infection • Binding to interferon receptors signals production of proteins with antiviral effects • Promote MHC-1 expression on infected cells • Activate NK cells to kill virally infected cells and produce cytokines

16. Local inflammatory response – the main players • Macrophages, mast cells and dendritic cells • Recognition of infection • Cytokines, Lipid mediators of inflammation • Complement • Interferons • Kinin system • Coagulation cascade

17. Kinin • Enzymatic cascade of plasma pro-enzymes that is triggered by tissue damage to produce inflammatory mediators including Bradykinin • Bradykinin causes increase in vascular permeability and pain

18. Local inflammatory response – the main players • Macrophages, mast cells and dendritic cells • Recognition of infection • Cytokines, Lipid mediators of inflammation • Complement • Interferons • Kinin system • Coagulation cascade

19. Coagulation system • Enzymatic cascade, triggered by blood vessel damage. • Activation results in the formation of a fibrin clot, prevents infectious microorganisms from entering the blood stream

21. Il-6 and shift to monocyte involvement • Il-6 produced by macrophages • Neutrophils shed their Il-6 receptors on entering site of infection • Endothelial cells can respond (via gp130) to Il-6 receptor/Il-6 complexes by decreasing the production of CXC chemokines and increasing production of CC chemokines such as MCP-1 and MCP-3 to attract monocytes

22. Systemic effects • TNF promotes catabolism of fat and muscle to release energy • IL-1 and IL-6 induce the liver to produce proteins involved in immunity and wound healing – the acute phase response • IL-1 and IL-6 act on the hypothalamus to induce fever and induce glucocorticoid release by the adrenals • Induction of leukocytosis

23. Figure 2-46

25. Figure 2-47

26. CRP • Pentraxin protein family • Binds phosphocholine of bacterial or fungal cell wall lipopolysaccharides • Oposonisation • Complement activation via C1q

27. Mannose-binding lectin • Normal low levels in serum, increased during acute-phase response • Opsonisation • Complement activation

28. Figure 2-45

29. Regulation • TNF induce the shedding of TNF receptors • Decreases sensitivity of that cell • Binds free TNF reducing availability to surrounding cells • Glucocorticoids stimulated via hypothalamus inhibit inflammation • Inhibition of inflammatory cytokine production • Antiinflammatory cytokines from macrophages • IL-10 produced following TLR stimulation of macrophages • TGFβ produced by macrophages (particularly those ingesting apoptotic cells) • Acetylcholine released by neurones of the vagus nerve act via nicotinic acetylcholine receptors on tissue macrophages to inhibit TNF and IL-1 production (explaination for action of acupuncture?)

30. Summary • Central role for macrophage • Recognition, phagocytosis, cytokine production • Local mediators of inflammation co-ordinated • Local and systemic inflammation require tight regulation