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THE
JOURNAL •REVIEW •www.fasebj.org
It’s time to redefine inflammation
Maria Antonelli and Irving Kushner
1
Division of Rheumatology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio, USA
ABSTRACT: Inflammation has been defined for many years asthe response to tissue injury and infection. We are now
forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflam-
mation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or
infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been
reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor
health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that in-
flammation is triggered by sentinel cells that monitor for tissue stress and malfunction—deviations from optimal
homeostasis—and that molecules that participate in the inflammatory process play a role in restoring normal
homeostasis. Accordingly, we suggest that inflammation be redefined asthe innate immune response to potentially
harmful stimuli such as pathogens, injury, and metabolic stress.—Antonelli, M., Kushner, I. It’s time to redefine
inflammation. FASEB J. 31, 1787–1791 (2017). www.fasebj.org
KEY WORDS: C-reactive protein •unfolded protein response •homeostasis •Claude Bernard •innate immunity
It is becoming nearly impossible to pick up a medical or
scientific journal and not find a report that inflammation is
implicated in yet another pathologic process. Gerald
Weissmann, in an essay published in The FASEB Journal a
few years ago appropriately entitled “It’s complicated,”
listed 12 conditions not accompanied by t he classic signs of
inflammation, for which inflammation has been held re-
sponsible (1), including atherosclerosis, obesity, depression,
Alzheimer’s disease, schizophrenia, and osteoporosis.
Among the conditions that can be added to this list are
asthma (2), insulin resistance (3), and type 2 diabetes (4).
Whatarewetomakeofthis?
Inflammation has always been a somewhat fuzzy,
loosely defined concept. As we suggested nearly 2 decades
ago, it is time to redefine the term “inflammation”(5). A
current textbook of pathology defines inflammation as “a
response…to infections and damaged tissues that bring
cells and molecules of host defense from the circulation to
the sites where they are needed in order to eliminate the
offending agents”(6). This definition defines inflammation
in terms of its stimulus and a limited view of its function.
Clearly, this definition is inadequate; many conditions
currently regarded as inflammatory, including those
mentioned in our first paragraph, occur without obvious
infection, damaged tissue, or an apparent “offending
agent.”The inflammation seen in acute gout is not trig-
gered by tissue injury or infection; nor are the auto-
inflammatory or autoimmune diseases.
We review the findings, as they have evolved through-
out history, which have led physicians to conclude that
inflammation is present; briefly survey some of the im-
mense variety of conditions that are currently felt to be
associated with inflammation; and discuss possible mech-
anisms that trigger inflammation in these conditions as
well as the presumed short and long term purposes of
the inflammatory process in different circumstances. We
conclude that there is a great variety of inflammatory
processes, if judged by stimuli, triggering mechanisms, and
functions. They differ enough that one might think it best if
they were regarded as separate entities, but it is probably
too late for that, in view of the ubiquitous use of the term
“inflammation”in recent years. Finally, we propose a def-
inition of inflammation, modified from that of Orozco et al.
(7), that reflects our current understanding.
HOW HAS INFLAMMATION BEEN RECOGNIZED
OVER TIME?
The term “inflammation,”derived from “flame,”owes its
name to the presence of warmth and redness, two of the
cardinal signs observed by Aulus Cornelius Celsus (ca.25
BC to ca. 50 AD)—rubor (redness), tumor (swelling), calor
(warmth), and dolor (pain)—in people with acute in-
flammation. Subsequently, varieties of what were called
inflammation began to be differentiated. We have long
been aware that inflammation did not always resolve, that
chronic inflammation might go on indefinitely, and that it
ABBREVIATIONS: CREBH, cyclic AMP response element-binding protein-
H; CRP, C-reactive protein; ER, endoplasmic reticulum; TLR, Toll-like
receptor; UPR, unfolded protein response
1
Correspondence: Division of Rheumatology, Case Western Reserve
University at MetroHealth Medical Center, 2500 MetroHealth
Dr., Cl ev el an d, Ohio, 44109 USA. E-mail: ixk2@case.edu
doi: 10.1096/fj.201601326R
0892-6638/17/0031-1787 © FASEB 1787
Vol.31, No.5 , pp:1787-1791, May, 2017The FASEB Journal. 174.100.218.47 to IP www.fasebj.orgDownloaded from
might take the form of persisting purulence, fibrosis, or
tissue destruction, as in abscesses or tuberculous cavities.
Thus, in a 1794 posthumous publication, A Treatise on the
Blood, Inflammation and Gunshot Wounds,thesurgeonJohn
Hunter (1728–1793) divided inflammation into 3 main
groups based on their gross appearance: adhesive, suppu-
rative, and ulcerative (8). Microscopy was introduced into
medicine in the middle of the 19th century, permitting
inflammation to be diagnosed histologically. It became
apparent that polymorphonuclear leukocytes were the
predominant cells involved in the early stages of acute in-
flammation, whereas cellular infiltrates largely consisted of
monocytes/macrophages and lymphocytes in chronic in-
flammation. A major change in our understanding of in-
flammation occurred during that era, when Rudolph
Virchow (1821–1902), the father of modern pathology, con-
cluded that there was not a single entity named “in-
flammation”but rather that there were various inflammatory
processes. He differentiated 4 kinds of inflammation—
exudative, infiltrative, parenchymatous, and proliferative—
and stressed the importance of the inflammatory stimulus.
He unsuccessfully wrestled with the definition of in-
flammation throughout his life and even considered used a
different term, but apparently none came to mind (9).
Our understanding of the mechanisms that mediate in-
flammation has expanded and accelerated markedly since
then, most notably in the last half century, and the criteria
for concluding that inflammation is present have changed
accordingly. A large number of ancient innate immune
mechanisms—the pattern recognition molecules that signal
the need to initiate an inflammatory response—have been
recognized. Some, such as Toll-like receptors (TLRs), rec-
ognize microorganisms (pathogen-associated molecular
patterns), and some recognize tissue injury (damage-
associated molecular patterns). Additionally, TLRs have
been found to play a role in other pathologic conditions such
as gout, in which TLR4 recognizes urate crystals. After en-
gagement of their ligands, an extraordinarily complex pro-
cess ensues—the innate immune response—culminating in
the activation of many genes that encode the proteins that
mediate and regulate inflammation. An army of mediators
may participate, including multiple cytokines, histamine,
bradykinin, prostaglandins, leukotrienes, platelet-activating
factor, complement components, inflammasomes, and a
family of cell adhesion–promoting molecules. In addition,
circulating markers of inflammation—acute phase proteins,
most notably C-reactive protein (CRP)—are produced by
hepatocytes in response to circulating cytokines (10).
LOW-GRADE INFLAMMATION
As a result, we now regularly conclude that inflammation
is present when increased concentrations of the elements
of the innate immune response are found (i.e., extracellular
mediators, such as inflammatory cytokines, or activation
of intracellular mediators, such as the transcription factor
NF-kB). In addition, it is now commonly concluded that
inflammation is present when concentrations of the acute
phase protein CRP are elevated, even if only modestly.
Indeed, CRP elevation, variously defined (11), is today
regarded virtually as a synonym for inflammation. As a
result, a new, not quite official entity has arisen, variously
referred to as “low-grade inflammation,”“subclinical in-
flammation,”or “microinflammation.”Low-grade inflam-
mation is not a consequence of tissue injury or infection,
Celsus’s classic signs of inflammation are not found, and
CRP levels are minimally elevated compared with those that
accompany acute inflammation after tissue injury or infec-
tion. Such modest CRP elevations (between 3 and 10 mg/L)
are found in about 30% of the American population (12).
What explains such a high prevalence of so-called low-
grade inflammation? Low-grade inflammation has been
reported to be associated with an astounding number of
conditions and lifestyles felt to be associated with poor
health; these conditions represent or reflect minor meta-
bolic stresses. The lengthy (partially cited here) list in-
cludes exposure to environmental irritants such as
cigarettes, secondhand smoke, sleep deprivation, low
levels of physical activity, atrial fibrillation, hypertension,
low birth weight, lumbar disc herniation, impaired cog-
nition, low grip strength, polycystic ovary syndrome,
living at high altitude (12, 13), prehypertension (14), ob-
structive sleep apnea (15), premenstrual symptoms (16), a
large variety of unhealthy diets (17), hypoxia (18), social
isolation (19, 20), being unmarried (21), and aging (22, 23).
QUALITY CONTROL IS ESSENTIAL TO
MAINTAIN HOMEOSTASIS
Human beings were not intelligently designed. Rather, we
were put together incrementally, building on preexisting
parts, by mutations, gene flow, genetic variation and re-
combination, in multiple steps, one might say haphaz-
ardly, over the course of millions of years. As the great
French biologist François Jacob pointed out, “Nature is a
tinkerer and not an inventor”: new sequences are adapted
from preexisting sequences rather than invented (24). As
one might expect in organisms that developed this way,
things do not always work smoothly. Very many quality
control mechanisms are required to prevent things from
going awry as a result of the minor perturbations, which
are part of daily life, that affect homeostasis. Thus, we have
a multitude of feedback loops, inhibitory molecules, the
unfolded protein response, heat shock proteins, etc.
Claude Bernard, the founder of experimental medicine,
brilliantly perceived that our cells live in a fairly constant
internal environment—the milieu int´
erieur (25). Late in his
life, he came up with this sweeping but valid statement: “All
of the vital mechanisms, however varied they may be, have
always but one goal, to maintain the uniformity of life in the
internal environment.”At first glance, it would seem that
inflammation is an exception to Bernard’s sweeping state-
ment because acute inflammation is accompanied by putting
aside the normal homeostatic settings and their replacement
by new set points, the acute phase response in the broad
sense. On reflection, “all of the vital mechanisms”does in-
deedincludeinflammation.Itisapparentthattheultimate
purpose of inflammation in response to tissue injury or in-
fection is to ultimately return tissues to their normal state,
including tissue repair and regeneration, which are the an-
atomic equivalent of metabolic homeostasis; cytokines ac-
tively participate in tissue repair (26).
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It is now clear that inflammation can also be induced by
tissue stress and malfunction in the absence of infection or
overt tissue damage (27). Low-grade inflammation occurs
when changes from the optimal internal environment lead
to stressed cells. Such deviations are recognized by macro-
phages, dendritic cells, and a variety of sentinel cells that
monitor tissue homeostasis. It has recently been found that
innate lymphoid cells also play a role in assuring tissue ho-
meostasis, although the mechanisms by which they recog-
nize metabolic or dietary stress and how they affect
homeostasis are poorly defined (28). Adjustments are then
made so that the normal homeostatic state is restored. We
now know that the inflammatory response in these instances
participates in the return to the optimal homeostatic state.
INFLAMMATION PARTICIPATES IN
RESTORING HOMEOSTASIS
The unfolded protein response (UPR), an essential adaptive
intracellular signaling pathway, is an instructive example of
the quality control mechanisms that respond to metabolic
stress in order to restore homeostasis (29). The endoplasmic
reticulum (ER) is the location in the cell where one third of
all newly synthesized proteins are folded, modified, sorted,
and transported to their ultimate location. Alterations in ER
homeostasis trigger UPR pathways with the goal of re-
storing homeostasis. Many metabolic stressors can create
ER stress, including glucose deprivation, perturbations of
intraluminal calcium levels, cytokines, altered cellular re-
dox state, hypoxia, toxins, viruses, increased protein traf-
ficking, and nutrient excess or deficiency (30). In response,
general protein translation is reduced and expression of
proteins that mark the targeted proteins for degradation is
increased. Once homeostasis is restored, global mRNA
translation resumes normally to allow cell survival.
Recent studies reveal connections between the UPR and
inflammation at multiple levels (31). The UPR results in
induction of many inflammation-associated genes, in-
cluding cytokines capable of acute-phase protein in-
duction. NF-kB, a master transcriptional regulator of
inflammation, can be activated by all 3 UPR pathways. ER
stress can activate the nod-like receptor family, pyrin
domain-containing-3 complex (NLRP3) (29). Obese adipose
tissue demonstrates up-regulation of inflammatory path-
ways leading to increased expression of TNF-aand IL-6 as
well as other mediators (32). Cyclic AMP response element-
binding protein-H (CREBH), a transcription factor similar
to activating transcription factor-6 (ATF-6; one of 3 sensors
lodged in the ER membrane that trigger the UPR), acts in an
especially liver-mediated acute phase response, resulting in
transcription of the acute-phase proteins CRP and hepcidin
(33–35).Inaddition,inresponsetometabolicstress,CREBH
plays a key role in maintaining lipid homeostasis by regu-
lating expression of the genes involved in hepatic lipogen-
esis, fatty acid oxidation, and lipolysis (36). Finally, calcium
released from the ER augments the production of mito-
chondrial reactive oxygen species (37).
It should not surprise us that molecules that participate
in the inflammatory process play a role in restoring normal
homeostasis. As we stated in 1998: “We often forget that
boundaries between various organ systems and between
categories of functional activity are merely man-made; an
attempt to impose conceptual order on biologic phenom-
ena. There is no a priori reason why nature should respect
these boundaries”(5). As Okin and Medzhitov (38) point
out, “Inflammatory mediators…act on target tissues and
alter their functional states, promoting …restoration of
tissue homeostasis.”Inflammatory signals can mediate
numerous variables in homeostasis systems via cytokines,
chemokines, biogenic amines, and eicosanoids (39), thus
influencing metabolism. For example, the inflammatory
cytokines TNF-aand IL-1bactivate lipolysis and inhibit
gluconeogenesis; TNF-amakes fat, liver, and skeletal
muscle less sensitive to insulin; and TNF-aand IL-1b
suppress expression of GLUT2 and glucokinase in pan-
creatic bcells, thus making them less sensitive to blood
glucose levels (39).
THE INFLAMMATORY PROCESSES AND A
PROPOSED DEFINITION
Acute and low-grade inflammation differ both pheno-
typically and in being triggered by different mechanisms
(Table 1). Acute inflammation is accompanied by the
TABLE 1. Comparison of acute, low-grade, and autoinflammatory inflammation
Parameter Infection Tissue injury Low-grade inflammation
Autoinflammatory
diseases
Cause Pathogens Trauma, tissue infarction Metabolic malfunction Usually spontaneous
Mediators Molecules and cells of the
innate immune response
Molecules and cells of
the innate immune
response
Molecules and cells of the
innate immune response
Molecules and cells
of the innate
immune response
Classic signs
of inflammation
+++ +++ None +++
CRP response +++ +++ + +++
Purpose Defense healing and repair Healing and repair Restoration of homeostasis None apparent
Triggering
mechanism
Pattern recognition
molecules, notably
for PAMPs and DAMPs
Pattern recognition
molecules, notably
for DAMPs
Sentinel cells that
monitor for tissue
stress, notably the UPR
Genetically based
dysregulation
DAMP, damage-associated molecular patterns; PAMP, pathogen-associated molecular pattern. Plus symbols indicate magnitude.
REDEFINING INFLAMMATION 1789
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classic signs of rubor, calor, tumor, dolor, and a substantial
acute phase protein response and has the immediate goal
of removing offending agents, removing necrotic tissue, and
restoring tissue integrity. Acute inflammation in response to
infection and tissue injury is triggered by pattern recogni-
tion molecules. In contrast, low-grade inflammation is not
accompanied by the classic signs of inflammation and
manifests a modest (at best) acute phase protein response.
Low-grade inflammation is triggered by sentinel cells that
monitor for tissue stress and malfunction, which are devia-
tions from the optimal homeostatic state. What do acute and
low-grade inflammation have in common? They share
many of the same effector molecules and cells and have the
same ultimate goal of restoring the normal, optimal ho-
meostatic state. We now know that acute gouty attacks are
triggered by binding of urate crystals to TLR4 (40). Yet an-
other species of inflammation, that seen in autoinflammatory
diseases, results from genetically based dysregulation of
suppressive components of the inflammatory response that
result in purposeless episodes of inflammation. Acute flares
of autoinflammatory diseases are usually not precipitated by
external stimuli. Autoimmune diseases may be regarded as a
variety of tissue injury in which the stimulus persists for
extended periods.
The boundary between normal adaptive homeostatic ad-
justments and inflammation is indistinct. It appears that there
is no sharp boundary between normal, quotidian adaptive,
homeostasis-restoring processes and inflammation. At what
pointdoweconcludethatitispathologic—that it is “in-
flammation”as we have understood it?
Inlightofthesesignificantdifferences, perhaps it would
be best if acute inflammation and low-grade inflammation
were regarded as separate entities. Indeed, the differences
between these entities are striking enough so that two lead-
ing investigators in the field have suggested a distinct no-
menclature for the latter state; both “para-inflammation”and
“metaflammation”(metabolically triggered inflammation)
have been proposed (30, 41). But it is probably too late; the
proverbial train seems to have already left the station. We
recognize that words have a range of meanings that change
with the times. In any case, if “low-grade inflammation”is to
be accepted as belonging in the “inflammation”category,
then a redefinition of inflammation is called for. We propose
a formulation modified from that used by Orozco et al.(7):
“Inflammation is the innate immune response to harmful
stimuli such as pathogens, injury and metabolic stress.”The
ultimate function of inflammation,inanycase,istorestore
the optimal homeostatic state, as, per Claude Bernard, is true
of all the body’s mechanisms.
ACKNOWLEDGMENTS
The authors thank David Samols, Nathan Berger, Stanley
Ballou, and Gary Kammer (Case Western Reserve University)
and John Volanakis (University of Alabama at Birmingham,
Birmingham, AL, USA) for helpful suggestions.
AUTHOR CONTRIBUTIONS
M. Antonelli and I. Kushner wrote and edited the
manuscript.
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Received for publication December 12, 2016.
Accepted for publication January 17, 2017.
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10.1096/fj.201601326RAccess the most recent version at doi:
2017 31: 1787-1791 originally published online February 8, 2017FASEB J
Maria Antonelli and Irving Kushner
It's time to redefine inflammation
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Vol.31, No.5 , pp:1787-1791, May, 2017The FASEB Journal. 174.100.218.47 to IP www.fasebj.orgDownloaded from
