Inflammation is vital for host defence against invasive
pathogens. In response to an infection, a cascade of
signals leads to the recruitment of inflammatory cells,
particularly innate immune cells such as neutrophils
and macrophages. These cells, in turn, phagocytose
infectious agents and produce additional cytokines
and chemokines that lead to the activation of lympho
cytes and adaptive immune responses. Similar to
the eradication of pathogens, the inflammatory
response is also crucial for tissue and wound repair
(BOX 1). Inflammation as a result of trauma, ischaemia–
reperfusion injury or chemically induced injury typically
occurs in the absence of any microorganisms and has
therefore been termed ‘sterile inflammation’. Similar to
microbially induced inflammation, sterile inflamma
tion is marked by the recruitment of neutrophils and
macrophages and the production of proinflammatory
cytokines and chemokines, notably tumour necrosis
factor (TNF) and interleukin1 (IL1).
Although inflammation is important in tissue repair
and eradication of harmful pathogens, unresolved,
chronic inflammation that occurs when the offending
agent is not removed or contained can be detrimental
to the host. The production of reactive oxygen species
(ROS), proteases and growth factors by neutrophils and
macrophages results in tissue destruction, as well as
fibroblast proliferation, aberrant collagen accumulation
and fibrosis. There are several examples of sterile inflam
matory diseases. Chronic inhalation of sterile irritants,
such as asbestos and silica, can lead to persistent activa
tion of alveolar macrophages and result in pulmonary
interstitial fibrosis1. In ischaemia–reperfusion injury, as
seen with myocardial infarction and stroke, the restoration
of blood flow causes further tissue destruction as a
result of neutrophilic infiltration, enhanced production
of ROS and inflammatory responses to necrotic cells2.
Sterile inflammation has also been implicated in such
disease processes as gout and pseudogout, in which the
deposition of monosodium urate (MSU) and calcium
pyrophosphate dihydrate (CPPD) crystals in the joints
results in acute neutrophilic infiltration followed by
chronic inflammation, fibrosis and cartilage destruc
tion3. In Alzheimer’s disease, neurotoxicity is associated
with activated microglial cells adjacent to βamyloid
containing plaques that generate ROS in addition to
proinflammatory cytokines4. Sterile inflammation
is also an important component of atherosclerosis, as
engulfment of cholesterol crystals by macrophages
leads to the activation and recruitment of inflamma
tory cells, endothelial cell dysfunction and plaque form
ation5. Finally, immune cell infiltration in the absence
of microorganisms is also characteristic of tumours,
and these cells can influence the growth and progres
sion of cancer6. Thus, understanding the mechanisms of
sterile inflammation is important for devising treatment
strategies against various human diseases.
As the inflammation induced in response to sterile
cell death or injury is similar to that observed during
microbial infection, host receptors that mediate the
immune response to microorganisms may be involved
in the activation of sterile inflammation. In the case
of infection, the mechanisms by which the inflam
matory response is initiated have been well studied.
There are several classes of receptors that are impor
tant for sensing microorganisms and for the subse
quent induction of proinflammatory responses (for a
*Department of Internal
Cancer Center, University of
‡Department of Pathology,
Comprehensive Cancer Center,
University of Michigan,
Michigan 48109, USA.
19 November 2010
An injury in which the tissue
first suffers from hypoxia as a
result of severely decreased,
or completely arrested, blood
flow. Restoration of normal
blood flow further enhances
exacerbates tissue damage.
Reactive oxygen species
(ROS). Oxygen radicals that
are mainly produced by the
chain. In excess, they can
cause intracellular and
which promotes cell death.
Sterile inflammation: sensing and
reacting to damage
Grace Y. Chen* and Gabriel Nuñez‡
Abstract | Over the past several decades, much has been revealed about the nature of
the host innate immune response to microorganisms, with the identification of pattern
recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the
conserved microbial motifs sensed by these receptors. It is now apparent that these same
PRRs can also be activated by non-microbial signals, many of which are considered as
damage-associated molecular patterns. The sterile inflammation that ensues either resolves
the initial insult or leads to disease. Here, we review the triggers and receptor pathways that
result in sterile inflammation and its impact on human health.
826 | DeCeMbeR 2010 | VOLUMe 10
© 20 Macmillan Publishers Limited. All rights reserved 10
An episode of acute cardiac
ischaemia that leads to death
of heart muscle cells. It is
usually caused by a thrombotic
A chronic disorder of the
arterial wall characterized by
endothelial cell damage that
gradually induces deposits of
cholesterol, cellular debris,
calcium and other substances.
These deposits finally lead to
plaque formation and arterial
A form of cell death that
frequently results from toxic
injury, hypoxia or stress.
Necrosis involves the loss of
cell integrity and the release
of cell contents into the
interstitium. This form of cell
death usually occurs together
with inflammation. Depending
on the context, the self
antigens that are released
by necrosis can become
review, see Ref. 7). These have been collectively termed
pattern recognition receptors (PRRs). These germline
encoded PRRs sense conserved structural moieties
that are found in microorganisms and are often called
pathogenassociated molecular patterns (PAMPs). Five
classes of PRRs have been identified to date: Tolllike
receptors (TLRs), which are transmembrane proteins
located at the cell surface or in endosomes; NODlike
receptors (NLRs), which are located in the cytoplasm;
RIGIlike receptors (RLRs), which are also located
intracellularly and are primarily involved in antiviral
responses; Ctype lectin receptors (CLRs), which are
transmembrane receptors that are characterized by
the presence of a carbohydratebinding domain; and
absence in melanoma 2 (AIM2)like receptors, which
are characterized by the presence of a pyrin domain and
a DNAbinding HIN domain involved in the detection
of intracellular microbial DNA8. Following ligand rec
ognition or cellular disruption, these receptors activate
downstream signalling pathways, such as the nuclear
factorκb (NFκb), mitogenactivated protein kinase
(MAPK) and type I interferon pathways, which result
in the upregulation of proinflammatory cytokines and
chemokines that are important in inflammatory and
It is now evident that PRRs also recognize non
infectious material that can cause tissue damage and
endogenous molecules that are released during cellu
lar injury (TABle 1). These endogenous molecules have
been termed damageassociated molecular patterns
(DAMPs), as these hostderived nonmicrobial stimuli
are released following tissue injury or cell death and
have similar functions as PAMPs in terms of their abil
ity to activate proinflammatory pathways. Here, we
discuss the nature of these instigators of inflammation
in the absence of infection, the potential mechanisms
by which they are recognized by the host to activate
inflammatory pathways and the implications for
DAMPs: indicators of tissue injury
A common feature of DAMPs is that they are endog
enous factors that are normally sequestered intracel
lularly and are therefore hidden from recognition by
the immune system under normal physiological condi
tions. However, under conditions of cellular stress or
injury, these molecules can then be released into the
extracellular environment by dying cells and trigger
inflammation under sterile conditions. The type of cell
death notably affects its immunogenicity and ability to
release immunostimulatory DAMPs. However, in gen
eral, DAMPs can be construed as signals of a potential
danger to the host9 (BOX 2). Necrosis usually occurs under
conditions of extreme damage (for example, ischaemia
or trauma) when apoptosis fails to occur. An important
consequence of necrotic cell death is the loss of plasma
membrane integrity, thereby allowing escape of intra
cellular material from the cell. Prototypical DAMPs
derived from necrotic cells include the chromatin
associated protein high-mobility group box 1 (HMGb1)10,
heat shock proteins (HSPs)11, and purine metabolites,
such as ATP12 and uric acid13 (TABle 1). In addition to
DAMPs from an intracellular source, there are also
extracellularly located DAMPs. These are typically
released by extracellular matrix degradation during
tissue injury. extracellular matrix fragments, such as
hyaluronan, heparan sulphate and biglycan, are gener
ated as a result of proteolysis by enzymes released from
dying cells or by proteases activated to promote tissue
repair and remodelling14. Similarly, in addition to intra
cellular molecules, intracellular stores of biologically
active proinflammatory cytokines and chemokines,
such as IL1α15 and IL33 (Ref. 16), may be released by
necrotic cells. Although these factors are not conven
tionally considered as DAMPs, they can mediate sterile
inflammatory responses (see below).
DAMPs have been identified by their ability
to induce inflammatory responses in vitro and/or
in vivo when purified and by the observed reduction
in inflammation when they are selectively depleted17.
However, in addition to the concern that the stimula
tory activity of some DAMPs is attributed to contami
nation of purified preparations with bacterial products,
important questions remain unanswered. It is unclear,
for example, whether some of the DAMPs that have
been identified based on their ability to stimulate
proinflammatory cytokine production in vitro have
a role in inducing sterile inflammation in vivo, as is
the case for HSPs11,18, S100 calciumbinding proteins19
and ATP20. Furthermore, many DAMPs, such as HSPs
and HMGb1, seem to interact with several receptors
(TABle 1) and, therefore, the significance of these inter
actions during sterile inflammation and disease patho
genesis remains to be fully elucidated. Also unknown
is the relative importance of individual DAMPs — that
Box 1 | Inflammation and wound repair
The acute inflammatory response has an integral role in normal wound healing and
tissue repair to eradicate the offending agent, regenerate the parenchyma and heal
any sustained damage. In response to injury that disrupts the parenchyma and causes
blood vessel damage, the coagulation system is activated, which begins the initial
stages of healing with the release of chemical mediators that promote vascular
permeability and leukocyte adhesion and recruitment. Activated platelets also
produce growth factors such as transforming growth factor‑β (TGFβ) and
platelet‑derived growth factor (PDGF), which activate fibroblasts and act as
chemoattractants for leukocytes116. The infiltration of leukocytes — first neutrophils,
followed by macrophages — allows the removal of dead cells and cellular debris. More
importantly, these cells secrete chemokines and cytokines, such as tumour necrosis
factor (TNF) and interleukin‑1 (IL‑1), that upregulate leukocyte adhesion molecules to
increase immune cell recruitment and induce the production of additional growth
factors and proteases by macrophages117. The release of proteases including matrix
metalloproteases leads to the degradation of the extracellular matrix to allow for
tissue remodelling. In addition to IL‑1 and TNF, growth factors and inflammatory
mediators produced by macrophages, such as fibroblast growth factor (FGF), PDGF,
prostaglandins and thrombospondin 1, promote new blood vessel growth, fibroblast
proliferation and collagen deposition117. Tissue remodelling is accompanied by
parenchymal regeneration or regrowth of the epithelial cell layer with resolution of
the healing process. Under conditions in which complete healing does not occur,
as in the setting of chronic infection or prolonged exposure to injurious agents, the
inflammatory response remains unresolved. Macrophages and neutrophils persist and
continue to secrete inflammatory cytokines, proteases and growth factors that lead to
inappropriate tissue destruction and scarring or fibrosis.
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VOLUMe 10 | DeCeMbeR 2010 | 827
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We apologize to our colleagues whose work was not cited or
was cited through others’ review articles because of space
limitations. Work in the authors’ laboratories is supported by
US National Institutes of Health grants CA133185 (G.C.),
and DK61707, AR051790, AI06331, AR059688 and
Competing interests statement
The authors declare no competing financial interests.
Gabriel Nuñez’s homepage: http://www.pathology.med.
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