Neutrophils

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Manifestation of Ghosts Exacerbates Asthma.

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Characterization, markers and antibodies

Neutrophil Recruitment and Activation

Neutrophils are the most abundant leukocyte found in the human blood stream and form the vanguard of the body’s cellular immune response. They develop in the bone marrow from granulocyte monocyte precursor (GMP) hematopoietic stem cells under the control of granulocyte colony-stimulating factor (G-CSF) in a process known as granulopoiesis, before being released into the blood stream. Circulating neutrophils are short lived (approximately five hours) but recruitment to sites of injury and/or infection can increase their lifespan significantly to several days.

The capture of neutrophils from the blood stream occurs at sites of inflammatory-activated endothelium, where the neutrophil engages with endothelial selectins, leading to rolling, before firmly adhering to the vascular wall via integrins and transmigrating to the tissue beneath (Vestweber 2007). This process is one of the mechanisms by which neutrophils are “primed” in readiness for activation (other mechanisms include exposure to early markers of inflammation including TNF-alpha and Interleukin 1-alpha) (Condliffe et al. 1998).

Using an array of cell surface receptors, the extravasated neutrophil is able to travel through the tissue by chemotaxis, following chemokine and/or pathogen-derived molecule concentration gradients to the site of injury (Griffith et al. 2014).

Diverse Mechanisms of Pathogen Destruction

Exposure to higher levels of inflammatory mediating molecules and/or pathogen derived molecules leads to neutrophil activation (Kolaczkowska and Kubes 2013), when the cell becomes able to attack microbes by a variety of mechanisms.

Firstly, neutrophils can recognize pathogens directly through pattern recognition receptors, or engage them by Fc or complement receptors to opsonized targets. The pathogen is then phagocytosed, where fusion with granules containing anti-microbial molecules and the generation of reactive oxygen species results in its destruction.

A second mechanism of microbe attack is degranulation, when granules discharge their contents directly into the milieu. The three types of granules were historically known as azurophilic or primary, specific or secondary, and gelatinase or tertiary, however it is now postulated that the different granule types are all part of a single continuum (Borregaard and Cowland 1997). The anti-microbial content of these granules include myeloperoxidase, defensins, cathepsins, lysozyme, gelatinases and serine proteases.

Finally, activated cells may produce neutrophil extracellular traps (NETs). During NETosis, the process of forming the NETs, nuclear swelling together with degranulation lead to the expulsion of DNA strands from the cell, forming a web with attached anti-microbial proteins. This mesh serves to both immobilize and destroy pathogens (Brinkmann et al. 2004). Even after NETosis, the remaining neutrophil cytoplast, devoid of DNA, remains in the tissue destroying pathogens by a mechanism such as phagocytosis. Due to their persistence in the tissue, these so called neutrophil cytoplast ghosts have been seen to have a role in inflammatory disorders such as ashma (Wills-Karp 2018). Read our blog “Manifestation of Ghosts Exacerbates Asthma” to learn more about this pathogenesis.

References

• Borregaard N and Cowland JB. (1997). Granules of the human neutrophilic polymorphonuclear leukocyte. Blood. 89, 3503-3521.
• Brinkmann V et al. (2004). Neutrophil extracellular traps kill bacteria. Science. 303, 1532-1535.
• Condliffe AM et al. (1998). Neutrophil priming: pathophysiological consequences and underlying mechanisms. Clin. Sci. (Lond). 94, 461-471.
• Griffith JW et al. (2014). Chemokines and chemokine receptors: positioning cells for host defence and immunity. Ann. Rev. Immunol. 32, 659-702.
• Kolaczkowska E and Kubes P. (2013). Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159-175.
• Vestweber D. (2007). Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol. Rev. 218, 178-196.
• Wills-Karp M (2018). Neutrophil ghosts worsen asthma. Sci Immunol. 3, 3, pii: eaau0112.