NDT Advance Access published online on April 5, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn171
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The great escape—myofibroblasts in fibrosis and the immune system*
Frank Strutz
Department of Nephrology and Rheumatology, Georg-August-University Medical Center, Göttingen, Germany
Correspondence and offprint requests to:
Frank Strutz, Department of Nephrology and Rheumatology, Georg-August-University Medical Center, Robert-Koch Str 40, 37099 Goettingen, Germany. Tel: +49-551-396981; Fax: +49-551-398906; E-mail: fstrutz{at}gwdg.de
Keywords: apoptosis; chronic renal failure; fas; fibroblast; fibrosis
 |
Fibrosis and myofibroblasts
|
|---|
The extent of renal interstitial fibrosis is one of the most
important prognostic factors in kidney biopsies and is a key
component of almost every form of progressive renal failure
[
1]. Similarly, fibrosis is also a morphological correlate of
progressive organ failure in liver, lung and heart. In all organs,
fibrosis is the result of a process called fibrogenesis in which
myofibroblasts (the name is due to the
de novo expression of
-smooth muscle actin in these cells whose expression is normally
restricted to vascular smooth muscle cells) are the key effector
cells [
2]. Myofibroblasts are formed via an intermediate form
entitled the ‘protomyofibroblast’ characterized
by the acquisition of contractile stress fibres [
3]. In the
kidney, myofibroblasts are derived mainly from activation of
resident interstitial fibroblasts, albeit differentiation processes
of periadventitial cells, mesenchymal stem cells or tubular
epithelial cells may play a role as well [
4]. Thus, myofibroblasts
may have several precursors, and similar mechanisms of myofibroblast
formation have been described in the liver [
5] and lung [
6].
However, it should be appreciated that not all matrix-synthesizing
cells are myofibroblasts and
vice versa that not all myofibroblasts
contribute to interstitial matrix deposition pointing to a certain
degree of heterogeneity of these cells [
3].
|
Myofibroblasts and the immune system
|
|---|
Myofibroblasts play a critical role in the resolution of inflammation
and scar formation. Whereas initial stimulation and proliferation
of these cells helps in confining inflammation and decreasing
tissue damage, continuous stimulation results in fibrogenesis
and eventually in the complete loss of organ function (reviewed
in [
4]). Thus, myofibroblasts need to be eliminated in order
to avoid major scar formation. Apoptosis was demonstrated to
be the key process in mediating the decrease in the number of
myofibroblasts during injury repair in the skin [
7]. In the
lung, survival of myofibroblasts is dependent on survival factors
such as the profibrotic cytokine TGF (transforming growth factor)-ß1
and on the Fas system [
8]. The Fas system consists of the Fas
receptor and the Fas ligand (FasL) [
9]. The Fas death receptor
triggers apoptosis when engaged by FasL. Besides TRAIL and TNF-
,
activation of the Fas system represents one of the major mechanisms,
through which one of the two pro-apoptotic pathways is induced
(the other being the stress pathway) [
10].
Figure 1 gives an
overview of how the Fas system induces programmed cell death.
In the lung, Fas-induced apoptosis, mediated primarily by T-lymphocytes
[
11], is one of the key mechanisms for maintaining tissue homeostasis
[
12].
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Fig. 1 The death receptor pathway. Caspases 3, 6 and 7 are the effectors of cell death that become activated by the death receptor pathway (shown here) or the stress pathway (not depicted). Binding of the Fas-ligand (FasL) to the Fas receptor is one way of activating the death receptor pathway. Others include the binding of TRAIL or TNF- to their respective receptors. Modified after [10].
|
|
Evasion of immune surveillance is a classic mechanism of tumour
formation in cancer cells where cells have been shown to resist
Fas-induced apoptosis [
13]. A number of years ago, Jelaska and
Korn described that resistance of myofibroblasts in the skin
to apoptosis induced by the Fas antibody may be responsible
for progressive disease in systemic sclerosis [
14]. Moodley
et al. detected that a similar mechanism may be responsible
for fibrosis in the lung. The group had isolated myofibroblasts
from patients with idiopathic pulmonary fibrosis and found that
these cells displayed a much higher resistance to Fas-induced
apoptosis compared to myofibroblasts isolated from normal lungs
[
15]. This potential mechanism was recently characterized in
further detail by Wallach-Dayan
et al. [
16]. Using the murine
bleomycin-induced model of pulmonary fibrosis, they paralleled
the studies by Moodley and confirmed that myofibroblasts isolated
from mice with pulmonary fibrosis were more resistant to Fas-induced
apoptosis despite overexpression of Fas itself in these cells.
The latter, seemingly contradictory fact, may be explained by
upregulation of the Fas signal inhibitor FLIP and/or release
of soluble FasL and/or lack of transmembrane death domains though
the exact mechanism was not examined by Wallach-Dyan
et al.
The overexpression of FasL resulted in an increased growth rate
of myofibroblasts from fibrotic lungs indicating a possible
growth advantage. Furthermore, the Fas/FasL interaction may
promote autocrine proliferation loops of myofibroblasts described
before in other organs as well. In addition, myofibroblasts
isolated from fibrotic lungs overexpressed a functional FasL
[
17] and were capable of mediating Fas/FasL-dependent apoptosis
in naïve thymocytes, activated primary T-cells and the
Jurkat T-cell line [
16]. Conversely, myofibroblasts isolated
from normal lungs did display only low-level FasL expression
and had no cytotoxic effect on T-cells. Thus, myofibroblasts
not only evaded cell death but also actively promoted apoptosis
of immune surveilling T-lymphocytes themselves. These results
were subsequently confirmed using FasL-deficient mice (to exclude
the effects of FasL-deficient haematopoietic cells, chimeric
gld mice were used, which contained wild-type lympoid organ
cells). Myofibroblast accumulation was markedly reduced in these
chimeric mice though neither the number of infiltrating CD3-positive
cells nor the amount of interstitial inflammation did differ
compared to control animals. Finally, using the air pouch model
as a model for immune tolerance, the authors confirmed robustly
prolonged survival of myofibroblasts isolated from fibrotic
lungs.
Figure 2 summarizes the findings of myofibroblast evasion
from immune surveillance as it has been demonstrated in the
lung. In addition, the same group had shown earlier that FasL-overexpressing
myofibroblasts may induce apoptosis in Fas receptor-positive
lung epithelial cells as an additional mechanism of organ destruction
in progressive scarring [
17].
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Fig. 2 Simplified scheme of the potential significance of FasL expression in myofibroblasts in pulmonary fibrosis. Myofibroblasts are generated mainly from resident fibroblasts via the intermediate form of protomyofibroblasts. FasL overexpression in myofibroblasts does confer resistance to apoptosis induced by T-lymphocytes as required for resolution of the scarring process. Conversely, FasL overexpressing myofibroblasts may induce apoptosis of T-lymphocytes themselves if they are Fas+. Uninhibited proliferation and matrix synthesis of these cells may subsequently result in organ fibrosis.
|
|
How are these findings transferable to the kidney? We do not
know yet. Ortiz
et al. found no expression of FasL in normal
murine interstitial fibroblasts [
18], but that may differ in
myofibroblasts from fibrotic kidneys. Thus, similar principles
as those described by Wallach-Dayan
et al. may apply for the
kidney, but we do need to study them. In addition, we do not
know how FasL expression is regulated in myofibroblasts. These
mechanisms will have to be analysed in order to better understand
the pathophysiology of progressive organ failure due to scarring.
|
Clinical implications
|
|---|
What are the clinical implications of these findings in pulmonary
scarring? The extent of renal fibrosis is a critical prognostic
parameter in every kidney biopsy. Interstitial matrix deposition
may progress despite the apparent resolution of the initiating
inflammatory process. The paper by Wallach-Dayan gives one more
explanation why this may be the case albeit these findings have
to be confirmed for the kidney. If confirmed, novel therapeutic
options may become available in the battle against chronic progressive
renal failure. These may include neutralizing antibodies against
FasL as has been evaluated in a murine model of chronic colitis
[
19] or more promising cell-specific interferences with the
signal transduction of the death receptor pathway as was recently
described as a promising approach for cancer therapy [
20]. However,
these putative therapies will have to be evaluated very carefully
since they interfere with many regulatory control mechanisms.
|
Conclusions
|
|---|
Myofibroblasts and the great escape. Myofibroblasts may be protected
from apoptosis in chronic scarring processes due to the killing
of Fas
+ lymphocytes allowing these cells to evade immune surveillance
and continuous matrix synthesis. This finding has to be verified
for the kidney and may point to novel ways of antifibrotic therapy.
Conflict of interest statement. None declared.
|
Notes
|
|---|
* Wallach-Dayan SB, Golan-Gerstl R, Breuer R. Evasion of myofibroblasts
from immune surveillance: a mechanism for tissue fibrosis. Proc
Natl Acad Sci USA 2007; 104: 20460–20465
|
References
|
|---|
- Bohle A, Strutz F, Müller GA. On the pathogenesis of chronic renal failure in primary glomerulopathies. Exp Nephrol (1994) 2:205–210.[Web of Science][Medline]
- Strutz F, Muller GA. Renal fibrosis and the origin of the renal fibroblast. Nephrol Dial Transplant (2006) 21:3368–3370.[Free Full Text]
- Hinz B, Phan SH, Thannickal VJ, et al. The myofibroblast: one function, multiple origins. Am J Pathol (2007) 170:1807–1816.[Abstract/Free Full Text]
- Strutz F, Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol (2006) 17:2992–2998.[Free Full Text]
- Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem (2007) 282:23337–23347.[Abstract/Free Full Text]
- Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol (2007) 293:L525–L534.[Abstract/Free Full Text]
- Desmoulière A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol (1995) 146:56–66.[Abstract]
- Phan SH. The myofibroblast in pulmonary fibrosis. Chest (2002) 122:286S–289S.[CrossRef][Web of Science][Medline]
- Dosreis GA, Borges VM, Zin WA. The central role of Fas-ligand cell signaling in inflammatory lung diseases. J Cell Mol Med (2004) 8:285–293.[Web of Science][Medline]
- Croce CM. Oncogenes and cancer. N Engl J Med (2008) 358:502–511.[Free Full Text]
- Stalder T, Hahn S, Erb P. Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol (1994) 152:1127–1133.[Abstract]
- Nagata S. Fas ligand and immune evasion. Nat Med (1996) 2:1306–1307.[CrossRef][Web of Science][Medline]
- Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science (1998) 281:1305–1308.[Abstract/Free Full Text]
- Jelaska A, Korn JH. Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum (2000) 43:2230–2239.[CrossRef][Web of Science][Medline]
- Moodley YP, Caterina P, Scaffidi AK, et al. Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. J Pathol (2004) 202:486–495.[CrossRef][Web of Science][Medline]
- Wallach-Dayan SB, Golan-Gerstl R, Breuer R. Evasion of myofibroblasts from immune surveillance: a mechanism for tissue fibrosis. Proc Natl Acad Sci USA (2007) 104:20460–20465.[Abstract/Free Full Text]
- Golan-Gerstl R, Wallach-Dayan SB, Amir G, et al. Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis. Am J Respir Cell Mol Biol (2007) 36:270–275.[Abstract/Free Full Text]
- Ortiz A, Ziyadeh FN, Neilson EG. Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. J Investig Med (1997) 45:50–56.[Web of Science][Medline]
- Dan N, Kanai T, Totsuka T, et al. Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol (2003) 285:G754–G760.[Abstract/Free Full Text]
- Safa AR, Day TW, Wu CH. Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy. Curr Cancer Drug Targets (2008) 8:37–46.[CrossRef][Web of Science][Medline]
Received for publication: 25. 2.08
Accepted in revised form: 5. 3.08
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Fibrosis and myofibroblasts
Myofibroblasts and the immune...