Cellular Communication and Inflammation

Cellular Communication and Inflammation

1. Cytokines

   • Activity
     • Autocrine
     • Paracrine
     • Endocrine
   • IL-4
     • B-cell
       • Activation
       • Proliferation
       • Differentiation
     • Thymocyte and Mast cell
       • Proliferation
   • IL-2 and IL-5
     • B-cell proliferation
   • IL-4 + IL-5
     • Induces B-cell class switch to IgE

2. Recognition and assessment

   • PRR activation
     • TLR receptors sense infection inside and outside the cell
       • TLR 4 and TLR1:TLR2 heterodimer sense bacterial infection outside the cell
       • TLR3 detects viruses
       • Horseshoe shaped
       • Transmembrane
       • Can be homo or hetero-dimers
   • Assessment
     • 1. Soluble pathogen-associated molecular patters (PAMPs) and dead microorganisms pose a low threat
       • Recognised by pattern-recognition receptors PRRs
       • Induces the production of pro-inflammatory cytokines (IL-6, IL-12 and TNF), as well as other cellular responses
       • PAMPs and microbial debris removed from the tissue
     • 2. Viable microorganisms, which are by definition infectious, pose a significant threat and elicit robust inflammatory responses
       • Bacterial viability is sensed through detection of 'vita-PAMPs', and possibly though other mechanisms
       • Leads to the activation of additional PRR pathways, including those involving interferon-regulatory factors, NOD-, LRR- and pyrin domain-comtainin 3
         • Induces IL-1-beta production and pyroptosis
       • Increased IFN-beta production
     • 3. Classical pathogens are extremely dangerous for the host organism and usually trigger immediate and strong inflammatory responses
       • PRR activation
       • Direct and indirect effects of virulence are sensed triggering rapid mobilisation of multiple PRR systems
         • Include TLRs and NLRs
       • Inflammatory response is scaled to the microbial threat

3. Activation of cytokine signalling and recruitment of neutrophils and diapedesis

   • General PRR activation activates an intracellular signal cascade that turns on relevant gene transcription of cytokines
   • Initiation of inflammatory response
     • Activated macrophages release pro-inflammatory cytokines
   • Neutrophils migrate to the site of inflammation by 'rolling'
     • Rolling along the capillary endothelium slows leukocytes down and facilitates stronger intractions
   • Diapedesis (extravation)
     • Neutrophils follow the IL-8 gradient to the site of the infection

4. Systemic signalling

   • Initiation of the inflammatory resopnse
     • Activated macrophages release pro-inflammatory cytokines
       • IL-6
         • Fever. Induces acute-phase protein production by hepatocytes
       • TNF-alpha
         • Activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues
         • Increased fluid drain to lymph nodes
         • Fever. Mobilisation of metabolites. Sock
         • 185 amino acid glycoprotein peptide released by many leukocytes
         • Increases vascular permeability for cells and humoral components (IgG and complement)
         • Also acts on hypothalamus
           • stimulates release of corticotropon releasing hormone (CRH)
           • suppresses appetite
           • Causes a fever
         • Enough TNF is good
         • Too much TNF is bad
       • IL-1-beta
         • Activates vascular endothelium
         • Activates lymphocytes
         • Local tissue destruction
         • Increases access of effector cells
         • Fever. Produciton of IL-6
       • CXCL8
         • Chemotactic factor recruits neutrophils and basophils to site of infection
       • IL-12
         • Activates NK cells