NEUTROPHILS

Neutrophils, belonging to the granulocyte group, are the most abundant white blood
cell found, with a normal range between 4000 to 11,000 cells/microL, approximately
50 – 70% of neutrophils circulating in the peripheral blood. They have a distinctive
feature of multi-lobed nucleus, with cell size of roughly a diameter ranged between 9
to 15 micrometers. Some of the several functions the neutrophils elicit are the first
line of defense for the innate immunity, mediators of inflammation, phagocytosis,
degranulation, and microbial clearance.

1. LIFE CYCLE
In a normal adult, a healthy bone marrow produces roughly 100 billion neutrophils
everyday. The precursor cells in the marrow takes about one week to mature into
a neutrophil. On the contrary, when the cells enter the bloodstream, they only
survive for less than 24 hours, but a few days longer in the tissues. However, the
bone marrow stores a substantial population of the cells as reserves, to prepare
for possible infections and inflammatory responses. Processes such as
proliferation, differentiation, and the egress into the circulation are influenced by
cytokines, transcription and growth factors. The neutrophils end their lifespan by
being ingested by macrophages through phagocytosis. Neutrophil homeostasis
remains at a relative constant due to a balance between production and
elimination.
Haematopoetic stem cells differentiate into multipotent progenitor cells and
subsequently into a lymphoid multipotent progenitor (LMPP). The LMPP then
differentiates into granulocyte-monocyte progenitor, in which under the influence
of granulocyte colony stimulating factor, becomes myeloblasts. It then undergoes
a chain of maturation processes which includes stages which are pro-myelocyte,
myelocyte, metamyelocyte, band cell, and matured neutrophil. The matured
neutrophils express multi-lobe morphology, various receptors, granules and
secretory vesicles. The granules in the neutrophils undergo metabolic processes
which releases hydrogen peroxide, a superoxide known for destroying
pathogens. Examples of enzymes stored in the granules include defensins,
myeloperoxidase, cathelicidins, and elastase.
2. RESPONSE TO A PATHOGEN

Neutrophils represent the first line of defence when faced with

pathogens by means of phagocytosis and release of degradation enzymes
contains in the granules of the cell. Phagocytosis is a process which involves
ingestion of pathogens into a phagosome, also known as the phagolytic
vacuole, in which matures into a phagolysosome. The process is enhanced by
the opsonization of pathogen with host proteins such as complement and
antibody. The degrading enzymes which have low pH properties aids in
destroying the pathogen. Direct interactions with the pathogens are through
pathogen-associated molecular patterns (PAMPs) by neutrophil pattern
recognition receptors (PRRs) which activates the signal transduction pathway
contributing to innate host defence. Lipoproteins, Lipoteichoic acid and
flagellins are some of the molecules belonging to PAMPs. Indirect interactions
occur through complement receptors or recognition of opsonised microbes by
Fc receptors.
Neutrophils also interacts with other immune and non-immune cells
such as the B and T cells, NK, CD4, CD8, endothelial, macrophages, dendritic
and mesenchymal stem cells. The activation of neutrophils stimulates the
generation of reactive oxygen species and the release of proteases which
leads to tissue damage. In terms of inflammatory responses, the cells are
stimulated to be released into the circulation towards the targeted affected
tissues. The cells then release cytokines upon arrival at site of inflammation.
An example of a neutrophil chemoattractant is the IL-8. Chemokines are
present in response to pro-inflammatory stimuli from cells such as fibroblasts,
mast cells, endothelial cells, epithelial cells and more. Leukotrienes and
prostaglandins also recruit neutrophils to target sites.
In cases where the pathogens are too large to be ingested, neutrophils
can produce neutrophil extracellular traps (NET), where DNA fibres and
proteins from the granules are required for the formation of the feature. The
NET forms an antimicrobial environment at targeted sites which contributes to
extracellular destruction of pathogens.

3. EXAMPLE OF DISEASE INVOLVING NEUTROPHILS

Neutrophilia
Neutrophilia is defined by an elevated absolute neutrophil count in the blood
in comparison to a normal reference range of neutrophil count. The normal
range is between 2500 – 7000 neutrophils/microL. The increase in absolute
neutrophil count is roughly 7700 neutrophils/microL and above, or two
 standard deviations above the mean. Neutrophil counts are known to express
diurnal variation, which peaks towards the late afternoon and slight elevations
following meals as well as emotional stress. Neutrophilia and granulocytosis
are often misused for each other, but the latter is differentiable due to the
elevations in basophils and eosinophils unlike neutrophilia which does not
involve the other granulocytes. The condition is usually linked to acute
inflammation, neoplastic conditions, chronic myeloproliferative leukemia are
among the few. The diagnosis of this condition can be done by a calculation
to obtain the absolute neutrophil count:

ANC = WBC x Percentage of Neutrophils x 100

Neutrophilia can be due to several pathologies such as a response to
allergies, infection or inflammations, demargination of neutrophils in the
bloodstream, increased production of neutrophils by the bone marrow, and
decreased egress from peripheral circulation to the tissues.
Etiologies of neutrophilia can be broken down to as follows:
a) Factitious neutrophilia
A condition due to the presence of artifacts in blood samples found during
laboratory works
b) Primary neutrophilia
Condition probably sourced from the impaired neutrophil regulation
causing bone marrows to stimulate elevated neutrophil production
c) Secondary neutrophilia
Condition usually linked to infections and inflammations in which toxic
granulations, Dohle bodies on peripheral smears can be observed. It may
also be triggered by a vast stimulus, some to note are emotional and
physical stress, asplenia, smoking, temperature changes, vigorous
exercise.

4. TREATMENT
The treatment for neutrophilia is to care for the underlying causes. For
leukemoid reactions with a worrying WBC count of more than 50 000,
cytotoxic therapy with hydroxyurea and aggressive hydration are given to
reduce complications.
Specific treatment options include tyrosine kinase inhibitor (TKI) therapy with
imatinib. This therapy prohibits bcr-abl tyrosine kinase, gene product of
 Philadelphia chromosome t (9;22) and the allogenic haematopoietic stem cell
transplant.
Antibiotic and anti-inflammatory therapies are considered for neutrophilia
associated with infection/inflammation. Specialists should recommend
treatment options, including antimicrobials, cytoreductive therapies,
leucopheresis, immunotherapy, and HCT.
Care should be taken to avoid medications prone to cause neutrophilia,
should it still be prescribed, medical officers need to carefully monitor and or
discontinue if complications arise.

REFERENCES
Britannica, T. Editors of Encyclopedia (2018, November 16). Neutrophil.
Encyclopedia Britannica. Retrieved on (2/1/2022):
https://www.britannica.com/science/neutrophil
Chabot-Richards, D., George, T. I. (2021, 8 October). Evaluation of neutrophilia.
BMJ Best Practice. Retrieved on (3/1/2022):
https://bestpractice.bmj.com/topics/en-us/1023
Hamill, T. (2017). Neutrophilia. Cancer Therapy Advisor, LabMed. Retrieved on
(3/1/2022): https://www.cancertherapyadvisor.com/home/decision-support-
in-medicine/labmed/neutrophilia/
Kobayashi, S. D., & DeLeo, F. R. (2009). Role of neutrophils in innate immunity: a
systems biology-level approach. Wiley interdisciplinary reviews. Systems
biology and medicine, 1(3), 309–333.
Masoumi-Dehshiri, R., Hashemi, A., Neamatzadeh, H., & Zare-Zardeini, H. (2014). A
Case Report: Acute Myeloid Leukemia (FAB M7). Iranian journal of pediatric
hematology and oncology, 4(4), 188–190.
Tahir N, Zahra F. (2021, September 19). Neutrophilia. StatPearls. Retrieved on
(4/1/2022): https://www.ncbi.nlm.nih.gov/books/NBK570571/
Rosales, C. (2018). Neutrophil: A Cell with Many Roles in Inflammation or Several
Cell Types? Frontiers in Physiology. Retrieved on (4/1/2022):
https://doi.org/10.3389/fphys.2018.00113
Rosales, C., Lowell C.A., Schnoor, M., Uribe-Querol, E. (2017). Neutrophils: Their
Role in Innate and Adaptive Immunity 2017. Journal of Immunology
Research. Retrieved on (4/1/2022): https://doi.org/10.1155/2017/9748345
Scher, J. U., et al. (2013). 11 - Neutrophils. Kelley's Textbook of Rheumatology
(Ninth Edition), 1(n.a.), 152-169.