© 2006 Nature Publishing Group
The function of the immune system is to prevent
the takeover of the body by genomes other than that
encoded in the germline1. Central to this function is
the ability to kill. Given the fundamental conservation
of biochemistry, there are few chemical mechanisms for
killing a given target cell that lack the potential to kill
some other life form2. Therefore, it is no surprise that the
neutrophil, one of the body’s main cellular components
for the destruction of microorganisms, also damages cells
and tissues of the host3,4. In fact, neutrophil-mediated
tissue damage at infected sites is so common that the
host takes stock of it when judging whether to mobilize
an immune response. Indeed, tissue injury is one of the
main sources of information that launches inflammation,
which in turn launches immunity.
To view immunology as the host’s participation in
the competition between genomes helps explain what
makes the neutrophil as fascinating as it is indispen-
sable5. Surprisingly, some immunologists seem not
to share this view. Say neutrophil, and they move on,
thinking: inflammation, not immunity. They disrespect
the cell’s ‘nonspecificity’ and consider its best-studied
behaviours — crawling, eating, and disgorging pre-
packed enzymes and partially reduced molecules of
oxygen — as rudimentary. Finally, scientists who are
interested in anti-inflammatory therapeutics are dis-
couraged from targeting neutrophils because it seems
futile to try to suppress neutrophil-dependent tissue
damage without the serious side effect of increasing the
host’s risk from infection1.
The aim of this article is to dispel each of those views.
The literature on neutrophils is so vast (PubMed finds
over 76,000 papers on the subject) that few authors have
attempted to cover it comprehensively6,7. This Review
makes no such effort. On the contrary, large chunks of
neutrophil biology are neglected here, including myelo-
poiesis, chemotaxis, transendothelial migration, synthe-
sis of lipid mediators and much of signal transduction.
Instead, selected studies are marshalled to support the
following five tenets: that the neutrophil often has an
important role in launching immune responses; that
the neutrophil helps to heal tissues as well as destroy-
ing them; that the neutrophil gives instructions with
as much specificity as a lymphocyte or neuron, albeit
with specificity of a different kind; that the neutrophil
integrates information, with a circuitry of awe-inspiring
design, to tailor its responses to its spatial and temporal
context; and that the neutrophil offers potential oppor-
tunities for selective pharmacological intervention, to
both promote and restrain inflammation.
Neutrophils as decision-shapers
Neutrophils help answer one of the central questions in
immunology: what triggers an immune response? The
danger theory holds that injured host cells release alarm
signals that activate antigen-presenting cells (APCs)8. The
pattern-recognition theory posits that ‘microbial non-self’
induces an innate immune response, which in turn trig-
gers an adaptive immune response9. Both views are valid,
but they leave much unexplained. For example, surgery
injures large numbers of host cells but does not promote
immune reactions to foreign compounds, such as anti-
biotics, that are present at the time. Non-pathogenic
resident microorganisms belonging to several thousand
Department of Microbiology
and Immunology, Weill Cornell
Medical College; and
Programs in Immunology and
and Molecular Biology, Weill
Graduate School of Medical
Sciences of Cornell University,
Box 57, 1300 York Avenue,
New York 10021, USA.
17 February 2006
A theory that the trigger for
mounting an immune response
consists of an injury to host
cells, resulting in the release
of alarm signals that activate
A theory that the trigger for
mounting an immune response
consists of the recognition of
‘microbial non-self’ molecules
by receptors expressed by
innate immune cells.
Neutrophils and immunity: challenges
Abstract | Scientists who study neutrophils often have backgrounds in cell biology,
biochemistry, haematology, rheumatology or infectious disease. Paradoxically,
immunologists seem to have a harder time incorporating these host-defence cells into
the framework of their discipline. The recent literature discussed here indicates that it
is appropriate for immunologists to take as much interest in neutrophils as in their lympho-
haematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune
responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms
that enrich our concepts of specificity, and offer exciting opportunities for the treatment
of neoplastic, autoinflammatory and autoimmune disorders.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 6 | MARCH 2006 | 173
© 2006 Nature Publishing Group
Secondary lymphoid organ
Immature DC or
αβ T cell or
γδ T cell
in the bone marrow
chemokine that is generated
proteolytic activation of its
precursor. Chemerin does not
yet have a ‘chemokine ligand’
Immature dendritic cells (DCs)
with a morphology resembling
that of plasma cells.
Plasmacytoid DCs produce
type I interferons in response
to viral infection.
species express pathogen-like microbial patterns, but they
only elicit maturation of the neonatal immune system10
and tolerance, not an immune response.
A third view is that a normal immune response
results from the ongoing detection of signals that report
injury and signals that report infection1. Although many
different molecular signals might be involved, they can
be considered ‘binary’ in the sense that most of them
arise as a consequence of one of these two events, and
it generally requires at least one signal from each class
to launch a response. This binary control begins with
inflammation. Except in autoinflammatory disorders,
the triggering and continuation of an inflammatory
response generally require the simultaneous receipt of
molecular signals directly or indirectly reporting tissue
damage and the presence of a genome different from
that of the host. Signals reporting injury and infec-
tion activate epithelial cells, mast cells, macrophages,
endothelial cells, platelets and neutrophils. Binary
signalling is propagated as these cells recruit, activate
and programme APCs through further binary signals,
such as cytokines and microbial products, cytokines
and CD40 ligation, or microbial products and products
of necrotic host cells. Finally, T cells are activated and
programmed by antigen-receptor ligation together with
signals from APCs, and B cells are activated by antigen-
receptor ligation together with signals from T cells.
Therefore, inflammation imprints the immune response
with a pattern of information flow: the integration of
signals of two or more distinct classes derived directly
or indirectly from injury and infection.
As a key component of the inflammatory response,
neutrophils make important contributions to the recruit-
ment, activation and programming of APCs (FIG. 1).
Neutrophils generate chemotactic signals that attract
monocytes and dendritic cells (DCs), and influence
whether macrophages differentiate to a predominantly
pro- or anti-inflammatory state11–13. For example, neutro-
phils proteolytically activate prochemerin to generate
chemerin, one of the few chemokines that attracts both
immature DCs and plasmacytoid DCs14. Neutrophils
also produce tumour-necrosis factor (TNF) and other
cytokines that drive DC and macrophage differentia-
tion and activation12,13,15. Neutrophil activation of DCs is
fostered by cell–cell contact, in which the specific carbo-
hydrates on CD11b engage DC-specific ICAM3-grabbing
non-integrin (DC-SIGN)15. Moreover, neutrophils secrete
TNF-related ligand B-lymphocyte stimulator (BLyS)16,
which helps to drive proliferation and maturation of
B cells, and interferon-γ, which helps to drive differen-
tiation of T cells and activation of macrophages17. On
a per-cell basis, neutrophils make fewer molecules of a
given cytokine than do macrophages or lymphocytes, but
neutrophils often outnumber mononuclear leukocytes at
inflammatory sites by one to two orders of magnitude,
and they can therefore be important sources of cytokines
such as TNF at the crucial juncture at which the deci-
sion is made to mount an immune response. However,
neutrophils can also function as powerful suppressors of
T-cell activation. For example, in patients with advanced
cancer, activated neutrophils can impair T-cell receptor
(TCR) ζ-chain expression and cytokine production18.
The ability of neutrophils to augment or inhibit lym-
phocyte expansion and activation at sites of inflammation,
draining lymph nodes and in the spleen is reciprocated
by the adaptive immune system’s control of the rate of
neutrophil production in the bone marrow. This can
be appreciated by looking upstream of the cytokine
granulo cyte colony-stimulating factor (G-CSF), which
is an essential regulator of neutrophil production
through several mechanisms. Stromal-cell-derived
G-CSF triggers bone-marrow neutrophils to release
matrix metallo proteinase 9 (MMP9), which solubilizes
KIT ligand, helping to mobilize progenitor cells19. G-CSF
also acts directly on the progenitors to increase their
proliferation, while suppressing stromal-cell expression
of CXC-chemokine ligand 12 (CXCL12, also known as
Figure 1 | Neutrophils interact with monocytes, dendritic cells, T cells and
B cells in a bidirectional, multi-compartmental manner. Through cell–cell
contact and secreted products, neutrophils recruit and activate monocytes, dendritic
cells (DCs) and lymphocytes, and products of monocytes, macrophages and T cells
activate neutrophils. Tissue macrophages ingesting apoptotic neutrophils produce
less interleukin-23 (IL-23). IL-23 triggers T cells in secondary lymphoid tissues to
produce IL-17. IL-17 triggers stromal cells in the bone marrow to produce granulocyte
colony-stimulating factor (G-CSF). G-CSF promotes proliferation of neutrophil
precursors and release of neutrophils into the circulation (see text for references).
BLyS, tumour-necrosis factor-related ligand B-lymphocyte stimulator; CXCL12,
CXC-chemokine ligand 12; IFNγ, interferon-γ; TNF, tumour-necrosis factor.
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I thank A. Ding, M. Fuortes, W. A. Muller and J. Upshaw for
critical reviews and apologize that the scope of the topic pre-
vented citation of many important studies. The Department of
Microbiology and Immunology acknowledges the support
of the William Randolph Hearst Foundation.
Competing interests statement
The author declares no competing financial interests.
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
Azurocidin | cathepsin G | G-CSF | MPO | protease 3 |
neutrophil elastase | PEPI | SLPI | TNF
Carl Nathan’s laboratory: http://www.med.cornell.edu/
See online article: S1 (box)
Access to this links box is available online.
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