Neutrophils Flashcards
Neutrophils are the least abundant of human leukocytes
TRUE OR FALSE
FALSE
Neutrophils are the MOST abundant of human leukocytes. (40-75%)
Neutrophils Morphology and Function:
- Up to 2x10^11 produced per day
- Short half life in circulation (hours)
- Inflammatory signals can prolong the lifespan
- During maturation in the bone marrow, neutrophils acquire a characteristic nuclear shape and many granules, filled with antimicrobial proteins
- Neutrophils are extremely important for host defense to infections
Mechanisms by which neutrophils kills microbes
- Phagocytes
- Degranulation
- NETs (Neutrophil Extracellular Traps)
Neutrophil maturation in the bone marrow:
Involves a complex interplay of transcription factors.
Key transcription factors for neutrophil differentiation:
- C/EBP family (especially C/EBP-a and C/EBP-e)
- Gfi-1
- PU.1
Key cytokine for neutrophil differentiation:
- G-CSF
Neutrophil trafficking from bone marrow:
- Large reserve of neutrophils stored in bone marrow
- Released when needed to fight infections (very quickly recruited)
- Neutrophils enter infected tissue and kill bacteria
- Neutrophils die in the tissue and are degraded by macrophages
- Macrophages can induce G-CSF production, thereby producing more neutrophils (A feed forward loop)
~12 hour circadian rhythm of neutrophils, driven back to the bone marrow as they get older.
Development of an inflammatory response is induced by local application of cytokine BLANK.
Development of an inflammatory response is induced by local application of cytokine IL-1beta.
Trafficking and Recruitment of Neutrophils Overview:
Bloodstream:
Circulating Neutrophils -> Rolling -> Adhesion -> Extravasation
Tissue:
Extravasation -> Chemotaxis
Extravasation = Movement of leukocytes out of circulatory system and towards infection.
Rolling is mediated by BLANKS
Rolling is mediated by SELECTINS
Selectin-mediated adhesion is weak and allows the neutrophil to roll along the vascular endothelial surface
Rolling slows the neutrophils down to allow integrin adhesion
Firm Adhesion is mediated via BLANKS
Firm Adhesion is mediated via INTEGRINS.
On neutrophils:
- Common b chain (b2)
- Variable a chain (alphaM, alphaL)
- alphaMb2 (Mac-1), alphaLb2 (LFA-1) [Integrins]
- Ligands include ICAM-1, Fibrinogen, denatured proteins, C3bi [Integrins bind to these ligands]
- Inside-out signalling via selectins and chemokines
Activation of integrins leads to stable, high affinity binding to ligands on other cells.
Neutrophil Chemotaxis:
Chemotaxis is directional migration of leukocytes:
- Essential for recruitment to sites of inflammation/infection after extravasation
- Mediated via chemotactic factors and chemokines
- Bind to G-protein coupled receptors (GPCRs) on neutrophils (chemokines receptors are all GPCRs in this case)
- Results in polarisation and directed movement
Chemotactic factors include:
- PAF, platelet activating factor
- fMLP – N-formylated peptides from bacteria and mitochondria
- C5a, C5 breakdown product, anaphylatoxin
Chemokines include:
-MIP-1, IL-8
Neutrophil Phagocytosis:
- Requires Pathogen Recognition e.g. by mannose receptors, scavenger receptors, LPS receptors, glycan receptor, CR3, CR4
- Neutrophils express receptors for many bacterial and fungal fungal constituents
Neutrophil Degranulation:
Granule Content reflects the proteins that are expressed at a certain differentiation stage. “targeting by timing hypothesis”
Granule types:
- Secretory vesicles: Integrins, cytokine/chemokine receptors, other receptors,…
- Tertiary/gelatinase granules: Matrix metalloproteinases (MMPs)
- Secondary/specific granules: Components of NADPH oxidase
- Primary/azurophilic granules: Proteases, myeloperoxidase, defensins
NETs (Neutrophil Extracellular Traps):
Neutrophils “Shoot” out their DNA to the extracellular space to trap bacteria.
Ros independent and dependent types.
Involves histone degradation .
Types of Extravasation:
Paracellular Extravasation: Between cells
Transcellular Extravasation: Through cells
Paracellular Extravasation is much more common.
