Neutrophil Receptors and signalling Flashcards
What is granulopoiesis?
The continuous production of neutrophils from precursor stem cells in the bone marrow
What is emergency granulopoiesis, and how is it triggered during systemic infection?
The mobilisation of additional neutrophils from the bone marrow when infections breach the local host defence
Driven by a cytokine: Granulocyte colony stimulating factor (G-CSF)
- Cells lining the blood vessels detect the systemic infection (via TLRs) and secrete G-CSF
- Neutrophils and their stem cells in the bone marrow express the G-CSF receptor leading to:
○ Differentiation and proliferation
○ Release from the bone marrow
- G-CSF also primes neutrophils and extends their lifespan (by limiting apoptosis)
How do tissue-resident macrophages initiate neutrophil recruitment?
Act as sentinels of infection
They respond by producing cytokines (e.g. IL-1-b, TNF-a) and chemokines (e.g. IL-8)
Proinflammatory cytokines (but also complement and histamine) act on local endothelium, upregulating adhesion molecules (e.g. selectins)
Endothelial cells can also respond directly to bacterial stimulation
Selectins initiate the first tethering of circulating neutrophils and locally inflamed endothelial cells
Tethering via selectins allows neutrophils to slow down and form important contacts with chemokines at the endothelial surface
How do chemokines (IL-8) induce further activation of the neutrophil?
Chemokines including IL-8 are anchored to the endothelial cell surface forming a chemotactic gradient
- Anchoring prevents chemokines being washed away in the blood flow
IL-8 is a classic neutrophil chemoattractant and induces further neutrophil activation via the CXCR1 and CXCR2 receptors
Neutrophils are ‘rolling’ along the endothelial surface
How do newly activated neutrophil adhesion molecules ensure firm adhesion?
IL-8 induces activation and upregulation of other neutrophil adhesion molecules including LFA-1 and MAC
IL-8 signals via its receptor causing a conformational change in integrins activating them to bind firmly to ICAM on endothelium
Ensures firm adhesion of neutrophils to the vessel wall
How does integrin adhesion activate neutrophils for transmigration?
Binding of neutrophil integrins to ICAM ligands also leads to outside in signalling
This prepares the neutrophil for transmigration by enhancing motility towards transmigration sites (typically endothelium cell junctions)
Signalling via integrins can also prime the respiratory burst, preparing neutrophils for pathogen encounter
Describe the process of the transmigration of neutrophils?
Chemokines including IL-8 are anchored to extracellular matrix proteins in the sub endothelial layer where they establish chemotactic gradients followed by neutrophils
Collagenase and MMPs can be mobilised from granules during diapedesis
Neutrophils use these to break down intercellular junctions and the sub-endothelial matrix
How do complement-derived C5a and bacterial fMLP peptides guide neutrophil chemotaxis?
fMPL - a peptide released from lysed and dying bacteria
C5a: an anaphylatoxin produced by proteolytic cleavage of C5 during activation of all arms pf the complement system
fMPL and C5a engage GPCR:
- Neutrophils mobilise along the concentration gradient towards the bacterium
Primes neutrophils in anticipation of microbial encounter
Describe the process of neutrophil swarming and what effect this has
Occurs when the first neutrophils make it to the scene and become activated. They express and secrete additional chemotactic molecules:
- Leukotreine B4 (LB4)
- IL-8
The initial neutrophils amplify the inflammatory response and encourage the arrival of additional neutrophils to enhance immunity
What are the major types of receptors expressed by neutrophils?
CD14: LPS receptor (non-opsonic)
Dectin-1: C-type lectin receptor for fungal glucan (non-opsonic)
CR3: receptor for complement C3b (opsonic), direct fungal receptor (non-opsonic), also acts as an integrin adhesion molecule
Fc receptors: receptor for Fc portion of IgG (opsonic)
What is the function of Fcγ receptors in phagocytosis?
Receptor for IgG
Receptors signal activation via ITAM and inhibition via ITIM
- Inhibitory receptors exist to keep inflammatory in check
They offer a convenient way for the innate immunity to utilise the breadth and specificity of the adaptive immune system
Act in synergy with CR3 for phagocytosis
What is the role of Dectin-1 in fungal pathogen recognition?
It is a non-opsonic receptor for fungal carbohydrates
Member of the C-type lectin family of receptors
Mediates phagocytosis of yeasts and fungi by macrophages and dendritic cells
Cooperates with TLRs to produce proinflammatory cytokines (e.g. TNF-a) in response to fungal pathogens
How do Toll-like receptors (TLRs) enhance neutrophil phagocytosis?
Enhance phagocytosis via other receptors
Important in priming neutrophils for subsequent phagocytic and microbicidal activity
Roles in regulating phagosome maturation, especially in dendritic cells
What is the “zipper” model of phagocytosis, and how does actin polymerization contribute to target engulfment?
In the zipper model receptors on the phagocyte surface engage ligands on the target microbe
The pseudopod continues to advance along the target surface so long as receptor ligand interactions occur
Actin polymerisation occurs at the pseudopod edge
