NEWS AND VIEWS
(2003).
5. Imai, Y. et al. Cell 105, 891–902 (2001).
6. Petrucelli, L. et al. Neuron 36, 1007–1019
(2002).
7. Darios, F. et al. Hum. Mol. Genet. 12, 517–526
(2003).
8. Lo Bianco, C. et al. Proc. Natl. Acad. Sci. USA 101,
17510–17515 (2004).
9. Winklhofer, K.F. et al. J. Biol. Chem. 278, 47199–
47208 (2003).
10. Chung, K.K. et al. Science. 304, 1328–1331
(2004).
11. Yao, D. et al. Proc. Natl. Acad. Sci. 101, 10810–
10814 (2004).
TLRs play good cop, bad cop in the lung
Luke A J O’Neill
Toll-like receptors act as mediators of injury or repair in the inflamed lung, and the balance depends on the integrity
of a component of the extracellular matrix (pages 1173–1179).
Inflammation, like most biological processes,
has a good side and a bad side. Understanding
the basis for the bad side has been a major area
of research, as dysregulation of the inflammatory process forms the basis of many diseases.
Acute inflammation underlies conditions such
as septic shock and acute respiratory distress
syndrome, whereas chronic inflammation
is a key feature of asthma and rheumatoid
arthritis. But inflammation also counteracts
infection, and has a role in repair after tissue
injury. This ‘good’ aspect of inflammation has
received less attention.
New findings by Jiang et al. in this issue
expand our understanding of the balance
between injury and repair during inflammation in the lung1. The authors report that the
inflammatory response in the lung is regulated
by Toll-like receptor (TLR)2 and TLR4, key
receptors in innate immunity that sense bacterial products and normally provoke inflammation2.
TLR2 and TLR4, they find, signal in response
to the extracellular matrix component hyaluronan, which fragments when lungs are
injured. TLR2 and TLR4 seem to drive inflammation in response to the fragmented form
of hyaluronan and protect lungs from inflammation-associated injury when hyaluronan is
in its high-molecular-mass form. The study
adds to evidence that TLRs have a role outside infection—they can also contribute to the
good side of inflammation, protecting tissue
integrity and allowing for repair.
Hyaluronan is a massive sugar polymer
and a key ‘shock-absorbing’ material in the
extracellular matrix. During inflammation,
hyaluronidases break down hyaluronan, gen-
The author is in the School of Biochemistry and
Immunology, Trinity College, Dublin 2, Ireland.
E-mail: [email protected]
a
b
Normal tissue
Extracellular
matrix
High-molecularmass hyaluronan
TLR2
Hyaluronan
fragments
TLR4
MyD88
Epithelial
cell
Injured tissue
MyD88
MyD88
Macrophage
Apoptosis
Lungs protected
Inflammatory
gene expression
Katie Ris
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
1. Braak, H. et al. Neurobiol. Aging 24, 197–211
(2003).
2. La Voie, M. et al. Nat. Med. 11, 1214–1221
(2005).
3. Cookson, M.R. Annu. Rev. Biochem 74, 29–52
(2005).
4. Feany, M.B. & Pallanck, L.J. Neuron 38, 13–16
Lungs injured
Figure 1 Jiang et al. found that TLR2 and TLR4 act as key sensors of the extracellular matrix
component hyaluronan in the lung. (a) High-molecular-mass hyaluronan is sensed by TLR2 and TLR4
in epithelial cells, maintaining the integrity of the epithelium by preventing apoptosis. (b) If hyaluronan
fragments are generated, the balance shifts away from high-molecular-mass hyaluronan. Inflammation
will result, again through TLR2 and TLR4. The status of hyaluronan in the lung is therefore sensed
by the TLR system, with high-molecular-mass hyaluronan protecting tissue and probably allowing for
repair, whereas hyaluronan fragments will provoke inflammation and cause injury. Altering the balance
may have therapeutic utility in the treatment of lung inflammation.
erating proinflammatory fragments in the 200
dalton range. The transmembrane receptor
CD44 helps clear hyaluronan from extracellular fluids and signals activation of NF-κB,
an inflammatory transcription factor3.
CD44 is clearly not essential for inflammatory signaling by hyaluronan, as hyaluronan
still induces expression of genes involved in
inflammation in macrophages from CD44deficient mice. A previous study had indicated
that TLR4 might be a signaling receptor for
hyaluronan4.
The current study built on that previous one,
beginning with a reexamination of the role for
TLRs in sensing hyaluronan. The authors first
examined the effects of hyaluronan fragments
NATURE MEDICINE VOLUME 11 | NUMBER 11 | NOVEMBER 2005
on chemokine production in macrophages
from mice deficient in MyD88—a molecule
essential for signaling by most TLRs. The
hyaluronan response was almost completely
abolished in these macrophages.
The authors next tested TLR2 and TLR4
double-knockout mice and found that they
were unresponsive to hyaluronan fragments.
Single-knockout mice were normal, implying
that both TLR2 and TLR4 are required for the
response. Importantly, the authors also tested
hyaluronan fragments purified from serum
of individuals with lung injury, in which the
level of such fragments is much higher than
in control serum. Again, proinflammatory
responses to these fragments were impaired
1161
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
NEWS AND VIEWS
in both MyD88 knockout and TLR2/TLR4
double-knockout mice.
The next part of the study examined the role
of MyD88, TLR2 and TLR4 in mice treated
with bleomycin, a noninfectious model
of lung injury. Bleomycin causes oxidantinduced damage and gives rise to high levels
of hyaluronan fragments in the lung. Given
that MyD88, TLR2 and TLR4 were required
for expression of genes involved in inflammation in response to hyaluronan fragments,
the authors expected there to be less injury
in response to bleomycin in lungs of MyD88
knockout and TLR2/TLR4 double-knockout
mice than in lungs of wild-type mice.
They got the opposite result—a marked
increase in lung injury in the knockout mice,
as measured by increases in interstitial thickness in lung tissue and protein accumulation
in bronchoalveolar lavage fluid. The increased
injury occurred despite there being less neutrophil infiltration in the lung tissue. The
data suggested that the hyaluronan fragments
generated in the bleomycin model were less
inflammatory in the knockout mice, but for
some reason the injury was more marked.
What might the mechanism be? Much of the
injury in the bleomycin-treated mice appears
to involve excess apoptosis, leading to a loss
of epithelial cell integrity. This response was
greatly enhanced in the TLR2/TLR4 doubleknockout mice, implying that these TLRs generate a signal to prevent apoptosis in epithelial
cells.
Not only do TLR2 and TLR4 hold back
apoptosis, they do so through hyaluronan—
but through a high-molecular-mass form
of the molecule. Mice treated with Pep-1, a
peptide that blocks hyaluronan binding, had
enhanced apoptotic injury in response to
bleomycin, as also seen in the TLR2 and TLR4
double-knockout mice. Moreover, selective
overexpression of hyaluronan synthase 2 in
the lung, leading to increased concentrations of high-molecular-mass hyaluronan,
protected mice from apoptosis in response to
bleomycin.
At first glance, these results appear confusing and even contradictory. What they reveal,
however, is an elegant system regulated by
TLR2 and TLR4. Depending on the form
of hyaluronan signaling through TLR2 and
TLR4, either lung inflammation or tissue
protection will result. High-molecular-mass
hyaluronan will prevent apoptosis of epithelial cells, thereby preventing lung injury during inflammation and ultimately promoting
repair. Low-molecular-mass fragments of
hyaluronan, produced as a result of injury,
will cause inflammation. Inflammation results
from TLR2 and TLR4 regulated expression
1162
of genes involved in inflammation in macrophages (Fig. 1).
A number of questions arise from the new
work. Whether hyaluronan in either form is a
direct ligand for TLR2 or TLR4 is not known.
Also unclear is why both TLRs are needed.
Do they synergize, and is signaling different
depending on the form of hyaluronan? Why
doesn’t high-molecular-mass hyaluronan
drive expression of genes involved in inflammation in epithelial cells and macrophages
as well as being antiapoptotic? The balance
between high-molecular-mass hyaluronan
and its breakdown into fragments is likely to
determine the balance between inflammationinduced injury and repair.
The work makes a compelling addition to
the literature, showing that in certain con-
texts TLRs protect tissues. Medzhitov and
colleagues have shown that in the gut, TLRs
protect the epithelium from injury by sensing commensal bacteria5. Here however there
is no microbial involvement, and the TLRs
instead sense the integrity of the extracellular
matrix. We are left with the intriguing possibility that manipulating the balance between
high-molecular-mass hyaluronan and its fragments might promote repair in the injured
lung or limit lung injury in inflammatory
diseases.
1. Jiang, D. et al. Nat. Med. 11, 1173–1179 (2005).
2. O’Neill, L.A.J. Sci. Am. 292, 24–31 (2005).
3. Fitzgerald, K.A. et al. J. Immunol. 164, 2053–2063
(2000).
4. Taylor, K.R. et al. J. Biol. Chem. 279, 17079–17084
(2004).
5. Rakoff-Nahoum, S. et al. Cell 118, 229–241 (2004).
Vaccinating transplant recipients
Jeffrey J Molldrem
Immunity is partly destroyed by the effects of high-dose chemotherapy
associated with hematopoietic stem cell transplantation. A new strategy
restores impaired immunity in people and offers clues to improving
vaccination against pathogens and tumors (pages 1230–1237).
High-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT)
is used to treat a variety of disorders, including multiple myeloma and lymphoma. After
transplant, immunodeficiency persists for a
year or more and can be even longer in allogeneic—or nonself—HSCT recipients who
receive additional immunosuppressive drugs
to prevent graft-versus-host disease.
Levels of antibodies, including those
against infectious organisms, usually decline
over the first year after HSCT. Immunization
against vaccine-preventable diseases is not
recommended before one year post-transplant because the response is poor. HSCT
recipients are therefore highly susceptible to
infection, particularly from opportunistic
organisms, and infection remains a leading
cause of death in these individuals.
In this issue, Rapoport et al. restore
immunity in people very early after HSCT.
The author is in the Section of Transplantation
Immunology, Department of Blood and Marrow
Transplantation, University of Texas M.D. Anderson
Cancer Center, Unit 900, Houston, Texas 772301429, USA.
E-mail: [email protected]
The approach involves in vitro expansion of
antigen-primed lymphocytes prior to HSCT,
and transfer back into the patient along with
vaccination against the antigen after HSCT1.
The idea is that by increasing the number of
lymphocytes and broadening the available
repertoire of antigen specificities early after
HSCT, subsequent vaccination could result
in early restoration of protective immunity.
HSCT was originally conceived to treat
hematopoietic malignancies by using high
doses of chemotherapy, sometimes in combination with radiation, that were intended to
be myeloablative. Reconstitution of the lymphohematopoietic system is then achieved
by transfer of allogeneic donor stem cells or
autologous cells that were collected before
chemotherapy. Increasingly, HSCT is being
used to treat immunodeficiency syndromes,
autoimmune diseases and solid tumors.
The reconstitution of immunity in the
recipient remains the most challenging aspect
of HSCT (Fig. 1). This is particularly true for
adaptive immunity because immune memory in the recipient—acquired over a lifetime
of exposure to infections and vaccines—is
lost during the preparative regimen. Passive
transfer of immunity is limited because donor
memory T and B cells in the graft are too few
VOLUME 11 | NUMBER 11 | NOVEMBER 2005 NATURE MEDICINE