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 2-5Pathogen 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 2-18The Complement Cascade

Figure 2-19Main 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