Neutrophils have long been regarded as the first line of defense against infection
and one of the main cell types involved in initiation of the inflammatory response.
It is generally accepted that the innate immunity functions of neutrophils are mainly
mediated by phagocytosis, release of granules, and formation of neutrophil extracellular
traps (NETs). In recent years, however, accumulating evidence has shown that neutrophils
possess greater functional diversity than previously appreciated. Thus, the classical
view of neutrophils as simple cytotoxic leukocytes against pathogens is currently
being revisited. Neutrophils display an array of biological functions important for
both innate and adaptive immune responses. Neutrophils can produce many cytokines
and chemokines upon stimulation, and in this way, they can interact with endothelial
cells, dendritic cells, macrophages, natural killer cells, T lymphocytes, and B lymphocytes.
Through all these interactions, neutrophils can either activate or downregulate both
innate and adaptive immunity. The novel functions of neutrophils reveal that these
cells have unanticipated roles in homeostasis, as well as in several diseases such
as atherosclerosis, stroke, chronic obstructive pulmonary diseases, and cancer.
To continue elucidating the complex role of neutrophils in infection, inflammation,
and immunity, this second special issue has brought together original and review articles
that will help us to better understand the complex and fascinating neutrophil biology.
As mentioned before, the primary role of neutrophils is the clearance of extracellular
pathogens, through phagocytosis, release of a broad array of effector molecules, and
the production of extracellular traps. However, some pathogens have also the capacity
to overcome neutrophil-mediated host defense mechanisms and establish infections leading
to disease. One such pathogen is the bacteria Staphylococcus aureus, which can block
chemotaxis and phagocytosis, thus evading killing by neutrophils. In addition, S.
aureus can survive within neutrophils and promote neutrophil cytolysis, causing the
release of molecules that promote local inflammation. The article by T.-S. Teng and
colleagues describes the mechanisms by which neutrophils kill extracellular pathogens
and how pathogens evade neutrophil defense mechanisms. They also discuss ideas that
might be useful for the development of novel therapies against infections caused by
antibiotic-resistant pathogens.
Similarly, the role of NETs is primarily to entrap extracellular microbes and, in
this way, to keep an early infection localized. Yet, besides microorganisms, other
stimuli can also activate neutrophils to produce NETs. The article by B. Rada summarizes
the recently described ability of different microcrystals to induce NET formation.
Microcrystals are insoluble crystals with a size of 1–100 micrometers that can irritate
phagocytes including neutrophils and typically trigger an inflammatory response. The
effect on neutrophils by microcrystals in adjuvant and by microcrystals associated
with diseases such as gout, atherosclerosis, and silicosis is discussed.
Neutrophils play an essential role during an inflammatory response. They are rapidly
mobilized from the circulation into damaged tissues. The blood supply of neutrophils
is at the same time replenished by a rapid recruitment of neutrophils from the bone
marrow to the vasculature. A great deal is known about the mechanism for neutrophil
migration into tissues. However, there is very little information about the molecular
signals that regulate the entry of neutrophils into the circulation. In an attempt
to learn more about this process, the article by C. Zuñiga-Traslaviña and colleagues
describes a zebrafish model, to assess the role of CXC-chemokines and CXC-receptor
2, in neutrophil migration into the blood circulation after injury. They found that
the CXCL8b/CXCR2 axis is an important regulator of neutrophil entry into the bloodstream.
On the other hand, when neutrophils arrive at sites of inflammation, they release
various cytokines. The signaling machinery required for production of inflammatory
and immunomodulatory cytokines and for extending the life of neutrophils at inflamed
sites is poorly known. Thus, this is another area of intense study in the neutrophil
field. The article by T. Ear and colleagues tells us about the constitutive expression
of various Src family kinase isoforms and of spleen tyrosine kinase (Syk) in neutrophils
and how the inhibition of these tyrosine kinases selectively blocks inflammatory cytokine
production by acting posttranscriptionally. In contrast, delayed apoptosis seems to
be independent of these kinases. These findings have implications for the future identification
of potential molecular targets that could be useful in therapeutic intervention of
chronic inflammatory conditions.
The involvement of neutrophils in several inflammatory pathologies is being recognized
more and more, with the growing understanding of the proinflammatory and immunomodulatory
properties of these cells. In some conditions, such as stroke and cancer, the numbers
of immune cells can significantly predict the clinical outcome of the disease. In
particular, the neutrophil-to-lymphocyte ratio was shown to predict hemorrhagic transformation
and the clinical outcome of stroke. However, the immunological mechanisms underlying
these effects are poorly understood. In the article by J. Ruhnau and colleagues, the
role of neutrophils in brain ischemia is discussed. Neutrophils are the first cells
to invade injured tissue after focal brain ischemia. In these conditions, they can
enhance tissue damage and even promote more ischemic injury by inducing thrombus formation.
Yet, neutrophils are also beneficial because they are involved in triggering the removal
of cell debris and are essential for defense against bacterial infections. Thus, therapeutic
interventions that target neutrophils to prevent stroke should preserve their functions
outside the central nervous system.
In other pathologies, neutrophils also play an essential role. For example, respiratory
diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized
by an excessive infiltration of neutrophils. It is generally accepted that subsequent
activation of these neutrophils promotes production of reactive oxygen species and
release of proteases resulting in tissue damage and alveolar airspace enlargement.
The article by J. Liu and colleagues reviews the role of neutrophils in respiratory
diseases, describing recent studies on mechanisms for neutrophil trafficking, activation,
and cell death. The studies on neutrophil function with isolated cells do not provide
a complete picture because cells are taken from the inflammatory environment of the
disease. Animal models play an important role in studying the underlying mechanisms
of respiratory diseases such as COPD as they address questions involving integrated
whole body responses. The article by G. Huang and colleagues presents a review of
the current animal models of COPD, focusing on their advantages and disadvantages
on immune responses and neutrophilic inflammation. Finally, the article by C. K. Mårdh
and colleagues discusses novel therapeutic approaches for respiratory diseases that
target neutrophil function. They describe how targeting the chemokine receptors CXCR2
and CXCR1 could be regulated during neutrophil trafficking and how targeting the enzyme
PI3K could modulate neutrophil function. Also, they explain how protease inhibitors
that target matrix metalloproteinases and neutrophil serine proteases could prevent
excessive tissue damage.
Together, these articles provide a sample of the multiple and complex functions of
neutrophils for fighting infections and for controlling immunity. They also underline
the relevant role of neutrophils in pathological conditions and provide guidance for
future research on the cell biology of these fascinating leukocytes.
Carlos Rosales
Clifford A. Lowell
Michael Schnoor
Eileen Uribe-Querol