title: FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling.
abstract: Scleroderma is a progressive autoimmune disease affecting multiple organs. Fibrosis, the hallmark of scleroderma, represents transformation of self-limited wound healing into a deregulated self-sustaining process. The factors responsible for maintaining persistent fibroblast activation in scleroderma and other conditions with chronic fibrosis are not well understood. Toll-like receptor 4 (TLR4) and its damage-associated endogenous ligands are implicated in immune and fibrotic responses. We now show that fibronectin extra domain A (Fn(EDA)) is an endogenous TLR4 ligand markedly elevated in the circulation and lesional skin biopsies from patients with scleroderma, as well as in mice with experimentally induced cutaneous fibrosis. Synthesis of Fn(EDA) was preferentially stimulated by transforming growth factor-β in normal fibroblasts and was constitutively up-regulated in scleroderma fibroblasts. Exogenous Fn(EDA) was a potent stimulus for collagen production, myofibroblast differentiation, and wound healing in vitro and increased the mechanical stiffness of human organotypic skin equivalents. Each of these profibrotic Fn(EDA) responses was abrogated by genetic, RNA interference, or pharmacological disruption of TLR4 signaling. Moreover, either genetic loss of Fn(EDA) or TLR4 blockade using a small molecule mitigated experimentally induced cutaneous fibrosis in mice. These observations implicate the Fn(EDA)-TLR4 axis in cutaneous fibrosis and suggest a paradigm in which aberrant Fn(EDA) accumulation in the fibrotic milieu drives sustained fibroblast activation via TLR4. This model explains how a damage-associated endogenous TLR4 ligand might contribute to converting self-limited tissue repair responses into intractable fibrogenesis in chronic conditions such as scleroderma. Disrupting sustained TLR4 signaling therefore represents a potential strategy for the treatment of fibrosis in scleroderma.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Zenshiro
authors.initials: Z
authors.lastname: Tamaki
authors.forename: Wenxia
authors.initials: W
authors.lastname: Wang
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.forename: Paul
authors.initials: P
authors.lastname: Hoover
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005353:Fibronectins / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D006801:Humans; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012594:Scleroderma, Localized / Q000097:blood / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D008024:Ligands; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; C572454:extra domain A fibronectin, mouse; C000593306:fibronectinEDA, human; D001761:Bleomycin; D003094:Collagen
references.citation: Hepatology. 2011 Jan;53(1):209-18
references.pmid: 20890893
references.citation: Exp Cell Res. 2010 Oct 1;316(16):2644-53
references.pmid: 20615404
references.citation: Am J Respir Crit Care Med. 2011 Sep 15;184(6):637-41
references.pmid: 21757624
references.citation: Mediators Inflamm. 2010;2010:
references.pmid: 20706656
references.citation: J Dermatol Sci. 2008 Feb;49(2):103-13
references.pmid: 17628443
references.citation: J Cutan Pathol. 2009 Sep;36(9):952-7
references.pmid: 19674200
references.citation: J Cell Biol. 1998 Aug 10;142(3):873-81
references.pmid: 9700173
references.citation: J Innate Immun. 2012;4(1):69-79
references.pmid: 21997473
references.citation: Int J Cancer. 1998 Oct 5;78(2):261-7
references.pmid: 9754661
references.citation: Circ Res. 2011 Mar 4;108(5):582-92
references.pmid: 21350212
references.citation: Expert Rev Mol Med. 2013 Aug 28;15:e9
references.pmid: 23985302
references.citation: Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15686-91
references.pmid: 23986498
references.citation: Integr Biol (Camb). 2012 Apr;4(4):410-21
references.pmid: 22410748
references.citation: Mol Cell Biol. 1999 Apr;19(4):2657-71
references.pmid: 10082532
references.citation: J Rheumatol. 1988 Feb;15(2):202-5
references.pmid: 3361530
references.citation: Am J Pathol. 2012 Apr;180(4):1340-55
references.pmid: 22387320
references.citation: Am J Pathol. 2013 Jan;182(1):192-205
references.pmid: 23141927
references.citation: Curr Drug Targets. 2006 May;7(5):567-77
references.pmid: 16719767
references.citation: Arthritis Rheum. 2010 Jun;62(6):1733-43
references.pmid: 20201077
references.citation: Methods Mol Biol. 2010;585:127-46
references.pmid: 19908001
references.citation: J Biol Chem. 2008 Feb 1;283(5):2858-70
references.pmid: 17967897
references.citation: Rheumatology (Oxford). 1999 Nov;38(11):1099-103
references.pmid: 10556262
references.citation: J Cell Mol Med. 2012 Nov;16(11):2647-54
references.pmid: 22469499
references.citation: Nat Rev Rheumatol. 2013 Aug;9(8):451-64
references.pmid: 23567456
references.citation: Fibrogenesis Tissue Repair. 2011 Sep 16;4:21
references.pmid: 21923916
references.citation: J Clin Invest. 2007 Mar;117(3):557-67
references.pmid: 17332883
references.citation: Scand J Gastroenterol. 2010 Mar;45(3):349-56
references.pmid: 20017652
references.citation: Eur J Pharmacol. 2008 Apr 14;584(1):40-8
references.pmid: 18299127
references.citation: Rheumatol Int. 2004 Jan;24(1):25-33
references.pmid: 12712258
references.citation: J Pathol. 2013 Jan;229(2):298-309
references.pmid: 22996908
references.citation: J Cell Biochem. 2013 Jun;114(6):1336-42
references.pmid: 23238947
references.citation: Am J Respir Crit Care Med. 2008 Mar 15;177(6):638-45
references.pmid: 18096707
references.citation: Transl Res. 2011 Apr;157(4):191-9
references.pmid: 21420029
references.citation: Clin Exp Rheumatol. 2004 Sep-Oct;22(5):617-20
references.pmid: 15485016
references.citation: J Pathol. 2013 Jan;229(2):145-56
references.pmid: 23097158
references.citation: J Am Soc Nephrol. 2011 Sep;22(9):1668-81
references.pmid: 21852586
references.citation: J Cell Biol. 2003 Jul 7;162(1):149-60
references.pmid: 12847088
references.citation: J Invest Dermatol. 2013 Aug;133(8):1979-89
references.pmid: 23677167
references.citation: Nat Rev Rheumatol. 2011 Oct 25;8(1):42-54
references.pmid: 22025123
references.citation: Biochem J. 1987 Nov 1;247(3):597-604
references.pmid: 3501287
references.citation: Eur Respir J. 1992 Apr;5(4):404-10
references.pmid: 1373389
references.citation: Exp Mol Med. 2009 Dec 31;41(12):858-65
references.pmid: 19745603
references.citation: J Cell Biol. 2010 Aug 23;190(4):693-706
references.pmid: 20733059
references.citation: Am J Pathol. 2009 Sep;175(3):1041-55
references.pmid: 19679873
references.citation: Biochim Biophys Acta. 2013 Jul;1832(7):1005-17
references.pmid: 23220258
references.citation: Immunol Rev. 2007 Dec;220:113-28
references.pmid: 17979843
references.citation: Ann Intern Med. 2010 Feb 2;152(3):159-66
references.pmid: 20124232
references.citation: J Surg Res. 2011 Jun 1;168(1):e61-9
references.pmid: 20089260
references.citation: J Cell Biol. 2009 Jun 29;185(7):1243-58
references.pmid: 19546243
references.citation: Arthritis Res Ther. 2005;7(5):R1113-23
references.pmid: 16207328
references.citation: J Invest Dermatol. 2004 Dec;123(6):1063-9
references.pmid: 15610515
references.citation: Am J Pathol. 1991 May;138(5):1257-65
references.pmid: 2024710
references.citation: Jpn J Cancer Res. 1999 Mar;90(3):320-5
references.pmid: 10359047
references.citation: J Biol Chem. 2003 Apr 4;278(14):12384-9
references.pmid: 12531888
references.citation: Arthritis Rheum. 2011 Jun;63(6):1527-33
references.pmid: 21360520
references.citation: Nat Med. 2007 Nov;13(11):1324-32
references.pmid: 17952090
references.citation: Curr Opin Rheumatol. 2013 Jan;25(1):65-70
references.pmid: 23143224
references.citation: J Biol Chem. 2002 Apr 26;277(17):14467-74
references.pmid: 11839764
references.citation: Stroke. 2012 May;43(5):1376-82
references.pmid: 22363055
references.citation: Cancer Res. 2007 Nov 15;67(22):10948-57
references.pmid: 18006840
references.citation: Nat Rev Immunol. 2008 Apr;8(4):279-89
references.pmid: 18340345
references.citation: Arthritis Rheum. 1980 May;23(5):581-90
references.pmid: 7378088
references.citation: FEBS Lett. 1988 Feb 8;228(1):42-4
references.pmid: 3422628
references.citation: Hepatology. 2008 Apr;47(4):1394-400
references.pmid: 18307210
references.citation: J Cell Biochem. 2003 Nov 1;90(4):709-18
references.pmid: 14587027
references.citation: J Pathol. 2008 Sep;216(1):1-14
references.pmid: 18680111
references.citation: J Am Soc Nephrol. 2010 Aug;21(8):1299-308
references.pmid: 20595685
references.citation: J Biol Chem. 2001 Mar 30;276(13):10229-33
references.pmid: 11150311
references.citation: Hepatology. 2012 Jun;55(6):1965-75
references.pmid: 22223197
references.citation: J Immunol. 1999 Apr 1;162(7):3749-52
references.pmid: 10201887
references.citation: J Leukoc Biol. 2007 Sep;82(3):657-65
references.pmid: 17575266