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

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

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

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

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

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

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.

Figure 2-39

Arachidonic acid-derived lipid mediators

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

Figure 2-18 The Complement Cascade

Figure 2-19 Main components of the Complement Cascade

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

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

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

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

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

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

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

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

Figure 2-46

Figure 2-47

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

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

Figure 2-45

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?)

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