Neutrophils Flashcards
What are factors that increase polymorphonuclear leukocyte numbers (PMN) ?
Stress, injury, infection, and increased cytokines
What happens in regulation of neutrophil production in steady-state and inflammation?
Steady state: increased C/EBP-alpha, decreased proliferation, increased granulocyte differentiation
Emergency: decreased C/EBP-a and increased C/EBP-ß, increased proliferation and increased granulation differentiation. There is a rapid expansion in the number of granulocyte to combat the infection.
What do neutrophils do and where are they stored?
Large reserves are stored within the bone marrow and are only released when there is an infection to fight. They travel to and enter the infected tissue, then engulf and kill the invading bacteria. They die in the tissue and are engulfed and degraded by macrophages.
What is the life timeline?
Storage -> Stimulation -> Circulation -> tissue -> circulation
What are the molecular players?
Rolling: Selectins and selectin conter receptors
Firm adhesion: activated integrins + Ig-like counterreceptors
Diapedesis: Integrins + endothelial cell adhesion molecules
Chemotaxis: integrins + chemokines/chemokine receptors
How do selectins mediate the rolling of leukocytes?
The adhesion is weal and allows the neutrophil to roll along the vascular endothelial surface until a selectin slows down the rolling which is then followed by the tight binding where is integrates into the infected cell (diapedesis) and then migrates.
What are ß2 integrins?
These are aphaß heterodimers that have a variable alpha chain with a common ß chain. There are three types, CD11a, b and c. The most important on neutrophils are a and b as they are the major adhesion receptors. They undergo a conformation change to high affinity via the chemokine ‘inside-out’ signalling which leads to a stable, high-affinity binding to ligands on other cells.
What is chemotaxis?
This is the direction migration of leukocytes. It is essential for recruitment to the sites of inflammation or infection. They are mediated by chemotactic factors and chemokines.
Bind to G-protein coupled receptors on the neutrophils which results in polarisation and the directed movement
How to neutrophils recognise pathogens?
By expressing receptors for many bacterial and fungal constituents such as CD14, CR4, glycan receptors, scavenger receptors, CR3, N-formyl-met receptor and mannose receptors
What are the primary opsonins
IgG, and complement factors C3 fragments C3b and C3bi.
Most microorganisms with not be phagocytosed without an opsinin. They work by pseudopods extending to cover the particle (only the bit that is opsonized.
Which complex leads to reactive oxygen species?
NADPH oxidase complex, this is assembled following the activation of neutrophils with diverse products (especially microbial derivities). This gives rise to ROS which are generated at the cell surface and within phagocytic vacuoles with superoxide anions - further reactions lead to formation of other antimicrobial ROS (e.g. hydroxyl radicals)
What is chronic granulomatous disease?
Recurrent or persistent infections of the soft tissue, lungs and other organs even with antibiotics. Caused by Stphylococcus aureus, burkholderia cepacia etc.
Symptoms: acne, inflammation of nares, gingivitis, early pneumonia, formation of granulomas in all tissues
Treatment: IFN-gamma with trimethoprimfulamethoxazole reduces frequency of infections.
Name three ways neutrophils kill microbes
Phagocytosis, degranulation and NETs
How do NETs work?
They de-condense the entire nuclear chromatin/DNA and release the structure into the cytoplasm to mix with granule-derived antimicrobial peptides before extruding the web-like structure into the ECM.
Requires activation of granule enzyme, formation of ROS and the neutrophil MT system and the actin cytoskeleton
Deficiency of NADPH-oxidase results in inhibition of NETs
potentially autoimmunogenic and associated with generation of anticitrullinated protein antibodies in seropositive rheumatoid arthritis
What are the two different types of NET formation?
Suicidal NETosis and Vital NETosis
