December 2007(II): S140 –S146
Inflammatory Mechanisms: The Molecular Basis of
Inflammation and Disease
Peter Libby, MD
Inflammation participates importantly in host defenses
against infectious agents and injury, but it also contrib-
utes to the pathophysiology of many chronic diseases.
Interactions of cells in the innate immune system, adap-
tive immune system, and inflammatory mediators orches-
trate aspects of the acute and chronic inflammation that
underlie diseases of many organs. A coordinated series
of common effector mechanisms of inflammation contrib-
ute to tissue injury, oxidative stress, remodeling of the
extracellular matrix, angiogenesis, and fibrosis in di-
verse target tissues. Atherosclerosis provides an example
of a chronic disease that involves inflammatory mecha-
nisms. Recruitment of blood leukocytes characterizes the
initiation of this disease. Its progression involves many
inflammatory mediators, modulated by cells of both in-
nate and adaptive immunity. The complications of estab-
lished atheroma, including plaque disruption and throm-
bosis, also intimately involve inflammation. Mastery of
the inflammatory response should aid the development of
novel strategies to predict disease susceptibility, target
and monitor therapies, and ultimately develop new ap-
proaches to the prevention and treatment of chronic
diseases associated with aging, such as atherosclerosis.
Key words: inflammation, cytokines, chronic disease,
atherosclerosis, macrophages, arterial lesions, plaque
rupture, thrombosis.
© 2007 International Life Sciences Institute
doi: 10.1301/nr.2007.dec.S140 –S146
INTRODUCTION
The recognition of inflammation dates back to an-
tiquity. As documented by Celsus in the 1st century AD,
Dr. Libby is Mallinckrodt Professor of Medicine at
Harvard Medical School and Chief of Cardiovascular
Medicine at Brigham and Women’s Hospital, Boston,
Massachusetts, USA.
Please direct correspondence to: Dr. Peter Libby,
Brigham and Women’s Hospital, 77 Avenue Louis
Pasteur, NRB 741, Boston, MA 02115, USA. Phone:
⫹1-617-525-4350, Fax: ⫹1-617-525-4999, E-mail:
plibby@rics.bwh.harvard.edu
S140
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the ancients understood that the tissue response to injury
gave rise to rubor (redness, due to hyperemia), tumor
(swelling, caused by increased permeability of the mi-
crovasculature and leakage of protein into the interstitial
space), calor (heat, associated with the increased blood
flow and the metabolic activity of the cellular mediators
of inflammation), and dolor (pain, in part due to changes
in the perivasculature and associated nerve endings).
Functio laesa (dysfunction of the organs involved)
joined as a fifth characteristic of inflammation in the
writings of Rudolf Virchow in the 1850s. In the late 19th
century, Elie Metchnikoff introduced the concept of
phagocytosis, a fundamental aspect of innate immunity,
after watching protozoa engulf particulate matter and
examining blood leukocytes ingest foreign bodies. In
1908, the Nobel Prize for Physiology of Medicine was
jointly awarded to Metchnikoff for this discovery and to
Paul Ehrlich for his work on humoral immunity, a key
component of adaptive immunity.
The aging of the population, the conquest of many
communicable diseases, and changing lifestyles present
an epidemic of chronic disease projected to soon extend
worldwide. Inflammation provides a unifying pathophys-
iological mechanism underlying many chronic diseases,
including diabetes, cardiovascular disease, certain can-
cers and bowel diseases, arthritides, and osteoporosis.
Common pathophysiologic scenarios apply to many of
these diseases.
INNATE AND ADAPTIVE IMMUNITY
The perspective of the 21st century affords de-
tailed knowledge of the cells and mediators that pro-
duce the characteristic signs of inflammation so
clearly observed by the ancients.1 Host defense mech-
anisms divide into two distinct, but inextricably
linked, pathways (Figure 1).
The innate immune response mounts a rapid re-
sponse to injury. It detects a broad range of molecular
patterns that are commonly found on pathogens but are
foreign to mammals, called pathogen-associated molec-
ular patterns (PAMPs), and thus lacks the exquisite
structural specificity of recognition by the adaptive im-
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Figure 1. Interplay between adaptive and innate immunity
during atherogenesis. The principal effector cell of innate
immunity, the macrophage (MF), elaborates cytokines that
critically regulate many functions of atheroma-associated cells
involved with disease initiation, progression, and complication,
as well as thrombosis. Interferon-␥ (IFN-␥), a product of the
activated T-cell, activates a number of these functions of the
macrophage. In turn, the activated macrophage expresses high
levels of major histocompatibility complex (MHC) class II
antigens, needed for antigen-dependent activation of T-cells.
Abbreviations: Th1, T helper cell type 1; Th2, T helper cell
type 2; SMC, smooth muscle cell. Reproduced from Hansson et
al.1 (Circ Res. 2002;91:281–291) with permission Lipppincott
Williams & Wilkins.
2,3
mune response. Macrophages express a set of pattern
recognition receptors including various scavenger recep-
tors and Toll-like receptors,4 whose ligands include
PAMPs such as lipopolysaccharides, surface phosphati-
dylserine, and aldehyde-derivatized proteins, as well as
modified forms of a classical risk factor for atheroscle-
rosis, low-density lipoproteins (LDL) modified by oxi-
dation or glycation.1 Ligation of scavenger receptors can
lead to endocytosis and lysosomal degradation of the
bound ligands,5,6 while engagement of Toll-like recep-
tors results in activation of nuclear factor-kappa B
(NF-⌲B) and mitogen-activated protein kinase (MAPK)
pathways.7,8 Ligation of Toll-like receptors can also
heighten phagocytosis, production of reactive oxygen
species, and release of cytokines, autacoids, and lipid
mediators that coordinate and amplify the local inflam-
matory response.9 –12
The other major limb of host defenses, the adaptive
immune response, mounts more slowly, and furnishes a
more finely focused response mechanism that requires
the recognition of specific molecular structures and de-
pends on the generation of large numbers of antigen
receptors, i.e., T-cell receptors and immunoglobulins, by
somatic rearrangement processes in blast cells.1 When
T-cells recognize a foreign antigen presented to them,
Nutrition Reviews姞, Vol. 65, No. 12
they initiate responses that target precisely that antigen,
including a direct attack against the antigen-bearing cell
by cytotoxic T-cells, stimulation of antibody production
by B-cells, and induction of a local inflammatory re-
sponse. T-cells can differentiate into at least two sub-
types of T helper (Th) cells. Th1 cells elaborate a number
of cytokines; among them, interferon-gamma (IFN-␥)
prominently coordinates crosstalk between innate and
adaptive limbs of the immune and inflammatory re-
sponses by stimulating the macrophage to increase its
production of a broad gamut of mediators including
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autacoids, reactive oxygen species, lipid species, and
pro-inflammatory cytokines.13,14 Th2 cells can stimulate
humoral immunity by elaborating a number of cytokines
that stimulate B-cell maturation into antibody-producing
plasma cells and promote B-cell class-switching to in-
crease production of immunoglobin E (IgE) antibodies.
Th2 cells can also aid recruitment and activation of mast
cells, another effector of allergic responses and contrib-
utor to chronic inflammation in a variety of tissues and
disease states. In addition to these specialized pro-in-
flammatory responses, Th2 cells can dampen the inflam-
matory response by elaborating cytokines with anti-
inflammatory properties such as interleukin-10 (IL-10).13
A GENERIC MODEL OF CHRONIC
INFLAMMATORY DISEASE
Traditionally, various subspecialties have claimed
the chronic diseases of various organ systems as their
own, and probed the pathophysiology in a reductionist
manner. Yet, from a synoptic perspective, many such
diseases have more mechanisms in common than usually
recognized or acknowledged. Indeed, a generic model of
chronic inflammatory disease is proposed that highlights
these shared pathophysiologic mechanisms. According
to this scheme, signals from the innate and adaptive
immune systems interact and converge on two prototypic
cell types: an epithelial cell and a mesenchymal cell of
the affected organs (Figure 2). These signals orchestrate
a repertoire of tissue responses such as recruitment of
leukocytes involved in chronic inflammation, extracellu-
lar matrix remodeling, cellular proliferation or death, and
angiogenesis (Figure 2). While diseases such as athero-
sclerosis, rheumatoid arthritis, cirrhosis, or interstitial
lung disease may manifest in very different ways, the
same fundamental mechanisms and mediators drive the
disease process.15,16 Helper T-cells abound in the lesions
of chronic inflammation in many organs, including ath-
erosclerotic plaques, rheumatoid synovium, and forms of
the chronic hepatidites, and in a number of pulmonary
diseases. The mononuclear phagocyte, cloaked variously
as a foam cell, osteoclast, histiocyte, microglia, or alve-
olar macrophage, also characteristically populates such
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Figure 2. Common inflammatory and immune processes act on different cell types, leading to different disease states.
Inflammatory and immune activity alters the function of various types of epithelial cells such as endothelial cells, synoviocytes,
enterocytes, glomerular/tubular epithelial cells, and bronchoalveolar cells, and each cell type characteristically participates in
the development of a different disease (atherosclerosis, arthritis, inflammatory bowel disease, kidney disease, and lung disease,
respectively). Inflammatory and immune processes may also act on different types of mesenchymal cells (e.g., smooth muscle
cells, fibroblasts, myofibroblasts, mesangial cells, or pericytes), leading to the development of chronic disease depending on the
specific cells targeted.

lesions. The epithelial cell involved depends on the
specific tissue involved—the vascular endothelial cell in
atherosclerosis, the enterocyte in inflammatory bowel
disease, and the glomerular or tubular epithelial cell in
renal disease. Similarly, inflammatory and immune
mechanisms involve different types of mesenchymal
cells depending on the organ—arterial smooth muscle
cells, fibroblasts, myofibroblasts, mesangial cells, syno-
viocytes, or pericytes.
The basic aspects of inflammation involve selective
and sequential migration of blood cells into tissues and
then local activation and interaction of these blood-based
cells with resident tissue cells. Some conditions display
only limited elements of the classic inflammatory pro-
cesses while in other conditions, key inflammatory me-
diators dominate but without the context of the classic
inflammatory mechanisms. For example, in Alzheimer’s
disease, blood cells do not migrate into the brain tissue,
but a resident monocytic cell, the microglial cell, acti-
vated locally expresses pro-inflammatory mediators and
can participate prominently in innate immune responses.
In osteoporosis, resident stromal cells primarily furnish
mediators such as IL-1, IL-6, and tumor necrosis factor-
alpha (TNF-␣) that regulate bone turnover unaccompa-
nied by other components of the classic innate immune
response.
Often a persistent stimulus coaxes a normal and
essential host defense mechanism into an injurious re-
sponse. Infection due to a pyogenic microbial pathogen
engenders an acute leukocyte response (e.g., polymor-
phonuclear cells) to clear the invading organism. Certain
intracellular pathogens including mycobacteria persist
and promote constant or repetitive injury, such as occurs
in atherosclerosis with exposure to ongoing oxidative
stress or sustained accumulation of modified lipoproteins
in the arterial intima.17,18 The resultant responses in
either case can, in time, impair the function of the organ
or tissue involved.
IMMUNE AND INFLAMMATORY
MECHANISMS IN THE INITIATION OF
ATHEROSCLEROSIS AND OTHER CHRONIC
DISEASES
To illustrate these general principles, consider ath-
erosclerosis. In their normal state, vascular endothelial
cells resist prolonged contact with leukocytes. However,
on exposure to an activating stimulus, be it modified
lipoproteins, microbial constituents, or pro-inflammatory
cytokines,17,18 the endothelium expresses a palette of
vascular cell adhesion molecule-1 (VCAM-1) and mem-
bers of the selectin family, P- and E-selectin.19 –23

S142 Nutrition Reviews姞, Vol. 65, No. 12

VCAM-1 binds monocytes and T-lymphocytes;19 P-se-
lectin binds monocytes and neutrophils;20,21 and E-selec-
tin binds neutrophils.22 After adhesion to the endothelial
surface, monocytes undergo directed migration into the
artery wall mediated by chemokines such as monocyte
chemoattractant protein-1 (MCP-1).17 Once resident in
the arterial intima, these recruited monocytes, upon ex-
posure to such activating and co-mitogenic mediators as
macrophage colony-stimulating factor (M-CSF), differ-
entiate into macrophages and proliferate.24 –26 The mac-
rophages over-express scavenger receptors and engulf
modified lipoprotein particles through endocytosis.27
Cholesteryl ester then accumulates in cytoplasmic drop-
lets in the macrophages, creating foam cells, considered
a hallmark of the nascent atherosclerotic plaque.27
PERPETUATION OF INFLAMMATION IN THE
PROGRESSION OF DISEASE
Once present and active in tissues such as the artery
wall, these cells of the innate immune system elaborate
reactive oxygen species, cytokines, procoagulants, and
other small molecules that amplify and sustain the in-
flammatory response. Resident local epithelial and mes-
enchymal cells both respond to pro-inflammatory signals
elaborated by the mononuclear phagocytes and, when
thus activated, can actively participate in propagating the
inflammatory response by generating a similar spectrum
of mediators as the “professional” phagocytes. In the
context of atherosclerosis, the relevant epithelial cell type
is the vascular endothelial cell and the mesenchymal cell is
the arterial smooth muscle cell. Early experiments exposed
endothelial cells to stimuli such as bacterial endotoxin or
recombinant human TNF, eliciting the expression of IL-1␤
and ␣.28 Subsequent work has filled out the palette of the
cytokines and other pathogenic proteins expressed by vas-
cular endothelium and smooth muscle, including IL-1␣,
IL-1␤, IL-6, IL-18, TNF, M-CSF, MCP-1, intercellular
adhesion molecule-1 (ICAM-1), and the procoagulant tis-
sue factor inter alii,29 –36 highlighting the two-way conver-
sation between the cells of the immune system and the
denizens of the organs they inhabit.
The inflammatory mediator CD40 ligand (CD40L or
CD154) has a particular place in perpetuating the inflam-
matory and immune responses during the development
and progression of atherosclerosis.37–39 Initial work by
immunologists identified the dyad of CD40L and its
receptor CD40 as a crux of cross-talk between the two
arms of the adaptive immune system, the humoral and
cellular responses. Engagement of B-lymphocyte CD40
by CD40L expressed on T-cells limits B-cell apoptosis
and signals maturation of the antibody response from
IgM to IgG.40 CD40 ligation also permits mutual ampli-
fication resulting in enhanced B-cell survival and plasma
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cell development, and activation of T-cells to produce
pro-inflammatory cytokines.40 More recent work local-
ized CD40 and its ligand to macrophages as well as
vascular smooth muscle and endothelial cells. CD40L
can regulate adhesion molecule, cytokine, and chemo-
kine expression, as well as coordinate processes involved
in matrix degradation and coagulation (e.g., tissue factor
expression).38,41,42 In addition to the classical pathway of
CD40 engagement, CD40L can bind to Mac-1.43
Studies in mice have illustrated the role of CD40L in
the progression of atherosclerosis. In one approach, LDL
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receptor-deficient mice received a neutralizing anti-
CD40L antibody treatment halfway through a 26-week
period of consumption of an atherogenic diet that virtu-
ally arrested the further progression of established ath-
erosclerotic lesions compared with controls (Figure 3).39
Further, CD40 inhibition also changed the composition
of the atherosclerotic lesions. Lesions in mice receiving
CD40L antibody had a higher content of smooth muscle
cells and collagen, and lower levels of macrophages and
lipids, characteristics associated in humans with plaque
stability.39 Other experimental approaches to interrupt-
ing CD40L function in mice yielded similar results.44
Figure 3. Anti-CD40L antibody treatment reduces lipid depo-
sition in the abdominal aorta of hypercholesterolemic mice.
Ldlr-deficient mice consumed a high-cholesterol diet for 13
weeks (A and B; white bar, diet only) before treatment with
either an irrelevant rat IgG (A and C; light gray bar), saline (A
and C; dark gray bar), or a rat anti-CD40L IgG antibody (A and
C; black bar, ␣-CD40L) for 13 weeks during continued regi-
men of the diet. Photomicrographs of tissue sections of longi-
tudinally cut abdominal aortas pinned out on black wax surface
and stained for lipid deposition with Sudan IV (B and C) were
analyzed by computer-assisted image quantification (shown are
mean 6 SD analyses; calculation of percent positive areas was
performed independently by two blinded observers; compari-
son between the respective study groups used Student’s t test)
(A). The thoracic section of the aorta is on the right. Representative
specimens from each group are shown. Reproduced from Schon-
beck et al.39 (Proc Natl Acad Sci USA. 2000;97:7458 –7463).
S143
INFLAMMATION CONTRIBUTES TO THE
THROMBOTIC COMPLICATIONS OF
ATHEROSCLEROSIS
Inflammatory and immune processes also contribute
to one of the ultimate complications of atherosclerosis,
an acute thrombotic event.17 The majority of myocardial
infarctions and some ischemic strokes result from plaque
rupture and the ensuing thrombus, a scenario that does
not require a tightly narrowed artery.45
The microanatomy of the mature atherosclerotic
plaque critically influences its clinical consequences. A
fibrous cap typically overlies and protects the plaque’s
highly thrombogenic lipid core from contact with the
coagulation factors in circulation.46 Plaques that have
ruptured and caused fatal coronary artery thromboses
tend to have thin fibrous caps.47,48
Interstitial collagen accounts for the biomechanical
integrity of the plaque’s fibrous cap. This extracellular
matrix macromolecule resists breakdown by most pro-
teinases. Only a select group of enzymes, members of the
matrix metalloproteinase (MMP) family, can make the
initial cleavage of this tightly wound triple helical mol-
ecule of collagen and initiate its catabolic pathway.
Macrophages, stimulated by T-cell-derived CD40L or
other pro-inflammatory cytokines, express members of
the MMP family,49,50 and may thus accelerate collagen
degradation in the inflamed atheroma.
Impaired collagen synthesis due to the actions of
pro-inflammatory cytokines on smooth muscle cells may
further compromise the integrity of the fibrous cap (Fig-
ure 4).49 For example, IFN-␥ released from T-cells
inhibits the expression of interstitial collagen mRNA,
resulting in decreased collagen synthesis by cultured
Figure 4. Simplified model illustrating the effects of inflam-
mation on the integrity of the plaque fibrous cap. Inflammation
within the arterial intima leads to signal exchange among the
T-cell, mononuclear phagocyte, and cells of the vessel wall.
This pathway leads to a weakening of the fibrous plaque
through decreased collagen synthesis or increased degradation.
IFN-␥ mediates decreased synthesis while increased break-
down is a result of proteinases induced by inflammatory sig-
naling. CD40 ligation augments the thrombogenecity of the
lipid core by expression of tissue factor, a major trigger of
thrombus formation. Adapted from Libby45 (Circulation
1995;91:2844 –2850).
S144
vascular smooth muscle cells. The T-cell may regulate
features of the plaque related to its propensity to rupture
through increased collagen degradation due to CD40-
mediated MMP expression by macrophages, and also
through decreased collagen formation as a result of the
action of IFN-␥ on smooth muscle.49 –51 Activated T
lymphocytes can also contribute to arterial thrombosis by
producing CD40L, which stimulates macrophages to
express the highly prothrombotic protein tissue factor.52
FUTURE AVENUES FOR INTERVENTION
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An improved understanding of the immune and
inflammatory processes responsible for the progression
of atherosclerosis has led to the proposal of novel strat-
egies to predict disease susceptibility. Although some
forms of imaging may help to reveal so-called “vulner-
able plaques,” we lack prospective studies validating
many imaging modalities proposed to predict plaque
complication (e.g., palpography, “virtual histology,” op-
tical coherence tomography, and computed tomographic
angiography).53,54 Some advocate testing of endothe-
lium-dependent vasodilation as a gauge for future
cardiovascular risk, but technical challenges preclude
the widespread adoption of this approach in multi-
center studies, and it lacks fidelity for reflecting the
clinical consequences of some interventions (e.g., es-
trogen and antioxidant vitamins). Measuring serum
markers of inflammation provides a promising strategy
for sharpening our ability to predict cardiovascular
events and guide and evaluate interventions. One such
blood marker of inflammation, C-reactive protein, has
gained support in this regard.55 Studies currently un-
derway will test the utility of this inflammatory bi-
omarker in targeting therapy.
CONCLUSIONS
Emerging laboratory and clinical data provide strong
evidence that inflammatory pathways contribute deci-
sively to the pathogenesis of a number of chronic dis-
eases associated with aging, and that these processes
involve common pro-inflammatory mediators and regu-
latory pathways. In atherosclerosis, increasing evidence
points to the importance of inflammatory processes in the
recruitment and activation of leukocytes and in endothe-
lial dysfunction, in the progression of the disease, and
ultimately in the thrombotic complication that very often
limits living well to age 100. We recognize increasingly
that many chronic diseases involve inappropriate deploy-
ment of host defenses critical to survival of the species
by favoring survival to reproductive age, but too often
inimical to individual longevity. By understanding the
common mechanisms, and shared mechanisms that or-
Nutrition Reviews姞, Vol. 65, No. 12
chestrate the array of dysfunction of our various organ
systems, we will be able to better predict susceptibility to
disease and gauge target therapies. Fortunately, lifestyle
measures such as abstinence from tobacco, a healthy
diet, and regular physical activity can often permit an
individual to stave off many of these inflammatory con-
comitants of aging, and lessen the likelihood that chronic
diseases will limit a long and healthy life.
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Nutrition Reviews姞, Vol. 65, No. 12