Initiation and resolution of inflammation Flashcards
Triggers for inflammation and cells that sense this
Pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). These bind to pattern recognition receptors (PRRs) that are expressed on sentinel cells (mast cells, macrophages, debdritic cells and epithelial cells) to sense danger.
Features of PAMPs and examples
Shared by classes of organism. Essential for the survival of the pathogen. Highly conserved. Absent from the certebrate host so allows the innate system to distinguish self from non-self.
Bacteria - LTA, peptidiglycan, lipoproteins, DNA, flagellin, lipopolyssacharide/LPS (only gram negative)
Viruses - coat protein, nucleic acid
Parasite - GPI anchor
Yeast - zymosan (β-glucan)
Overview of pattern recognition receptors
Detect PAMPs. Germ-line encoded. Located where pathogens or their componetns reside. Present at the cell surface (CLRs, TLRs), in endosomes (TLRs), in the cytosol (NLRs, RLRs), and in the circulation
Toll like receptors - function and the most potent of them
10 functional human TLRs. Recognise features typical of bacteria, fungi, viruses and parasites. They activate transcription factors like NF-κB, AP-1 and interferon-regulatory factors (IRFs). Bacterial products tend to activate NF-κB and AP-1 and stimulate pro inflammatory cytokine and chemokine production. Viral nucleic acids tend to stimulate IRFs which induce antiviral type 1 interferons (IFNα and IFNβ). TLR4 is the most potent activator of the immune system (ligand is LPS of gram negative bacteria
Can be homo or heterodimers. Are located at the plasma membrane or in endosomes. Tend to detect microbial protein, carbohydrates and lipoprotein products at the cell surface (have to be at the right location to detect particular pathogens). Detect microbial nucleic acid in endosomes..
a) C-type lectin receptors (CLR)
b) RIG-I-like receptors (RLRs)
c) Cytosolic NOD-like receptors (NLR)
a) Important in fungan infections
b) detect viral RNA in the cytoplasm
c) These cytoplasmic receptors may recognise both PAMPs and DAMPs. Mutations in NOD2 (recognises muramyl dipeptide found in most bacteria) are associated with Crohn’s disease (inflammatory bowel disease). NLRP3 forms part of a cytosolic inflammasome (detects lots of PAMPs/DAMPs), linked to disease such as atherosclerosis, gout and type 2 diabetes. Inflammation is induced by caspase 1 activating IL-1 (see image)
Effects of cytokines secreted by activated macrophages (5)
IL-1β: Locally - activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effect cells. Systemically - causes fever and production of IL-6
TNF-α: Locally - activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes. Systemically - fever, mobilisation of metabolites, shock
IL-6: Locally - lymphocyte activation, increased antibody production. Systemically - fever, induces acute-phase protein production
CXCL8: Locally - chemotactic factor that recruits neutrophils, basophils and T cells to site of infection
IL-12: Locally - activates NK cells, induces the differentiation of CD4 T cells into Th1 cells
Recruitment of leukocytes to the sites of infection
Rolling adhesion - leukocyte carbohydrate binds to selectin on endothelium
Tight binding - CXCL8 receptor on leukocyte binds to CXCL8 chemokine that is expressed on infected endothelium surface. Also, LFA-1 receptor on leukocyte binds to ICAM-1 on endothelium
Diapedesis - leukocytes move through junctions between endothelial cells
Migration - into blood vessel and around circulation
Pathway of local infection vs systemic infection (sepsis) of bacteria
Localised response - Macrophages activated to secrete TNFα in the tissue. Increased release of plasma proteins into the tissue. Increased phagocyte and lymphocyte migration into tissue. Increased platelet adhesion to blood vesel wall. Phagocytosis of bacteria. Local vessel occlusion. Plasma and cells drain to local lymph node.
Systemic infection (sepsis) - Macrophages activated in the liver and spleen secrete TNFα into the bloodstream. Systemic oedema causing decreased blood volume, hypoproteinaemia, and neutropenia, followed by neutrophilia. Decreased blood volume causes collapse of vessels. Disseminated intravascular coagulation (blood clots in small blood vessels) leading to wasting and multiple organ failure (loss of blood perfusion).
Resolution of inflammation and repair
The acute inflammatory response requires tight control. Removal of the inflammatory stimulus. Many mediators have short half-lives, natural decline. Neutrophils are short lived and die by apoptosis. As inflammation proceeds, stop signals are produced: i) macrophages switch from pro-inflammatory to anti-inflammatory lopid bio-effectors (lipoxin). Triggered by engulfment of apoptotic neutrophils ii) lipid mediated class-switch involves many cells (prostaglandins and leukotrienes are produced by many cells eg endothelial cells, neutrophils, monocytes and macrophages) iii) macrophages switch to anti-inflammatory cytokines such as IL-10 and TGFβ
Replacement of damaged and dead tissue to granulation tissue
1) Recruit fibroblasts to lay down ECM
2) Recruit endothelial cells to form new blood vessles
3) Remodel ECM to form strengthened scar tissue
Role of macrophages in controlling the repair process
Phagocytose debris including RBCs, apoptotic neutrophils, dead organisms. Recruit fibroblasts (FGF, fibroblast growth factor) which lay down new ECM, firstly collagen in linear strands. Recruit endothelial cells (VEGF, vascular endothelial growth factor) to form new blood vessels. Secrete metalloproteinases to allow remodelling of ECM, changing from just linear strands which are only strong in one direction, to a criss-cross pattern which is strong in all directions
When does chronic inflammation occur
When causative agent responsible for inflammation isn’t removed, so the processes of repair and inflammation continue together. i) injurious agent is endogenous (stomach acid causing peptic ulcer) ii) injurious agent may be non-degradable eg silica or dust particles iii) injurious agent may evade host defences eg tuberculosis iv) host may attack self components (autoimmunity).
Chronically activated macrophages stimulate fibroblasts and collagen production. Scar tissue develops (fibrosis).
