The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against β1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of β1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung. 1. Introduction Tissue regeneration comprises dedifferentiation of adult cells into a stem cell state and the development of these cells into new remodelled tissue, identical to the lost one. Tissue repair is defined as replacement of normal tissue by fibrous tissue and integrins are crucial in these processes. Integrins are membrane spanning proteins facilitating the two-way communication between the inside and outside of a cell. Integrins have the capacity to bind a multitude of molecules both inside and outside of the cell. The binding of these molecules results in the transmission of information into and out of the cell, which can influence a host of different cellular functions, including the cells metabolic activity. Of the many types of integrin receptors, the β1 integrin is by far the most ubiquitous allowing cells to detect a vast array of stimuli ranging between toxins, protein hormones, neurotransmitters, and macromolecules. There have been numerous publications documenting a potential role of β1 integrin in tissue development and repair in several tissue types (reviewed in [1]). It is clear that β1 integrin plays a crucial role during postnatal skin development and wound healing, with the loss of epithelial β1 integrin causing extensive skin blistering and wound healing defects. More recently, there has been active interest in the cosmeceutical development of β1 integrin targeting formulations. One such example is following the discovery of fucoidans from Fucus vesiculosus and its effect on skin scarring and ageing [2, 3] which was later found to be mainly attributed to alpha2 and β1 integrin [4]. Integrins in general, including β1 integrin, exhibit global structural rearrangement and exposure of ligand binding sites
References
[1]
R. Al-Jamal and D. J. Harrison, “Beta1 integrin in tissue remodelling and repair: from phenomena to concepts,” Pharmacology and Therapeutics, vol. 120, no. 2, pp. 81–101, 2008.
[2]
T. Fujimura, Y. Shibuya, S. Moriwaki et al., “Fucoidan is the active component of Fucus vesiculosus that promotes contraction of fibroblast-populated collagen gels,” Biological and Pharmaceutical Bulletin, vol. 23, no. 10, pp. 1180–1184, 2000.
[3]
T. Fujimura, K. Tsukahara, S. Moriwaki, T. Kitahara, and Y. Takema, “Effects of natural product extracts on contraction and mechanical properties of fibroblast populated collagen gel,” Biological and Pharmaceutical Bulletin, vol. 23, no. 3, pp. 291–297, 2000.
[4]
T. Fujimura, S. Moriwaki, G. Imokawa, and Y. Takema, “Crucial role of fibroblast integrins α2 and β1 in maintaining the structural and mechanical properties of the skin,” Journal of Dermatological Science, vol. 45, no. 1, pp. 45–53, 2007.
[5]
M. Shimaoka and T. A. Springer, “Therapeutic antagonists and conformational regulation of integrin function,” Nature Reviews Drug Discovery, vol. 2, no. 9, pp. 703–716, 2003.
[6]
J. C. Friedland, M. H. Lee, and D. Boettiger, “Mechanically activated integrin switch controls α5β1 function,” Science, vol. 323, no. 5914, pp. 642–644, 2009.
[7]
M. Kato and M. Mrksich, “Using model substrates to study the dependence of focal adhesion formation on the affinity of integrin-ligand complexes,” Biochemistry, vol. 43, no. 10, pp. 2699–2707, 2004.
[8]
B. H. Luo, K. Strokovich, T. Walz, T. A. Springer, and J. Takagi, “Allosteric β1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain,” Journal of Biological Chemistry, vol. 279, no. 26, pp. 27466–27471, 2004.
[9]
M. Shimaoka, J. Takagi, and T. A. Springer, “Conformational regulation of integrin structure and function,” Annual Review of Biophysics and Biomolecular Structure, vol. 31, pp. 485–516, 2002.
[10]
J. Takagi, B. M. Petre, T. Walz, and T. A. Springer, “Global conformational earrangements in integrin extracellular domains in outside-in and inside-out signaling,” Cell, vol. 110, no. 5, pp. 599–611, 2002.
[11]
H. Xia, D. Diebold, R. Nho et al., “Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis,” Journal of Experimental Medicine, vol. 205, no. 7, pp. 1659–1672, 2008.
[12]
N. Koyama, J. Seki, S. Vergel et al., “Regulation and function of an activation-dependent epitope of the β1 integrins in vascular cells after balloon injury in baboon arteries and in vitro,” American Journal of Pathology, vol. 148, no. 3, pp. 749–761, 1996.
[13]
M. W. Johansson, S. R. Barthel, C. A. Swenson et al., “Eosinophil β1 integrin activation state correlates with asthma activity in a blind study of inhaled corticosteroid withdrawal,” Journal of Allergy and Clinical Immunology, vol. 117, no. 6, pp. 1502–1504, 2006.
[14]
S. Wright, N. L. Malinin, K. A. Powell, T. Yednock, R. E. Rydel, and I. Griswold-Prenner, “α2β1 and αVβ1 integrin signaling pathways mediate amyloid-β-induced neurotoxicity,” Neurobiology of Aging, vol. 28, no. 2, pp. 226–237, 2007.
[15]
H. Ni and J. A. Wilkins, “Localisation of a novel adhesion blocking epitope on the human β1 integrin chain,” Cell Adhesion and Communication, vol. 5, no. 4, pp. 257–271, 1998.
[16]
D. L. Brown, D. R. Phillips, C. H. Damsky, and I. F. Charo, “Synthesis and expression of the fibroblast fibronectin receptor in human monocytes,” Journal of Clinical Investigation, vol. 84, no. 1, pp. 366–370, 1989.
[17]
M. Ticchioni, C. Aussel, J. P. Breittmayer, S. Manie, C. Pelassy, and A. Bernard, “Suppressive effect of T cell proliferation via the CD29 molecule: the CD29 mAb 1 “K20” decreases diacylglycerol and phosphatidic acid levels in activated T cells,” Journal of Immunology, vol. 151, no. 1, pp. 119–127, 1993.
[18]
A. A. Porollo, R. Adamczak, and J. Meller, “POLYVIEW: a flexible visualization tool for structural and functional annotations of proteins,” Bioinformatics, vol. 20, no. 15, pp. 2460–2462, 2004.
[19]
A. Chigaev, A. Waller, O. Amit, L. Halip, C. G. Bologa, and L. A. Sklar, “Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation,” Journal of Biological Chemistry, vol. 284, no. 21, pp. 14337–14346, 2009.
[20]
A. Chigaev, T. Buranda, D. C. Dwyer, E. R. Prossnitz, and L. A. Sklar, “FRET detection of cellular α4-integrin conformational activation,” Biophysical Journal, vol. 85, no. 6, pp. 3951–3962, 2003.
[21]
X. Trepat, L. Deng, S. S. An et al., “Universal physical responses to stretch in the living cell,” Nature, vol. 447, no. 7144, pp. 592–595, 2007.
[22]
U. Cavallaro, J. Niedermeyer, M. Fuxa, and G. Christofori, “N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling,” Nature Cell Biology, vol. 3, no. 7, pp. 650–657, 2001.
[23]
G. E. Hannigan, C. Leung-Hagesteijn, L. Fitz-Gibbon et al., “Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase,” Nature, vol. 379, no. 6560, pp. 91–96, 1996.
[24]
M. D'Amico, J. Hulit, D. F. Amanatullah et al., “The integrated-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways,” Journal of Biological Chemistry, vol. 275, no. 42, pp. 32649–32657, 2000.
[25]
M. Delcommenne, C. Tan, V. Gray, L. Rue, J. Woodgett, and S. Dedhar, “Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 19, pp. 11211–11216, 1998.
[26]
Y. Shikata, K. Shikata, M. Matsuda et al., “Integrins mediate the inhibitory effect of focal adhesion on angiotensin II-induced p44/42 mitogen-activated protein (MAP) kinase activity in human mesangial cells,” Biochemical and Biophysical Research Communications, vol. 261, no. 3, pp. 820–823, 1999.
[27]
A. Chigaev, A. M. Blenc, J. V. Braaten et al., “Real time analysis of the affinity regulation of α 4-integrin: the physiologically activated receptor is intermediate in affinity between resting and Mn2+ or antibody activation,” Journal of Biological Chemistry, vol. 276, no. 52, pp. 48670–48678, 2001.
[28]
R. Barsacchi, C. Perrotta, P. Sestili, O. Cantoni, S. Moncada, and E. Clementi, “Cyclic GMP-dependent inhibition of acid sphingomyelinase by nitric oxide: an early step in protection against apoptosis,” Cell Death and Differentiation, vol. 9, no. 11, pp. 1248–1255, 2002.
[29]
D. K. Sharma, J. C. Brown, Z. Cheng, E. L. Holicky, D. L. Marks, and R. E. Pagano, “The glycosphingolipid, lactosylceramide, regulates β1- integrin clustering and endocytosis,” Cancer Research, vol. 65, no. 18, pp. 8233–8241, 2005.
[30]
S. Filosto, S. Castillo, A. Danielson et al., “Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury,” American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 3, pp. 350–360, 2011.
[31]
M. A. Fernàndez, C. Albor, M. Ingelmo-Torres et al., “Caveolin-1 is essential for liver regeneration,” Science, vol. 313, no. 5793, pp. 1628–1632, 2006.
[32]
M. A. del Pozo, N. Balasubramanian, N. B. Alderson et al., “Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization,” Nature Cell Biology, vol. 7, no. 9, pp. 901–908, 2005.
[33]
R. D. Singh, E. L. Holicky, Z. J. Cheng et al., “Inhibition of caveolar uptake, SV40 infection, and β1-integrin signaling by a nonnatural glycosphingolipid stereoisomer,” Journal of Cell Biology, vol. 176, no. 7, pp. 895–901, 2007.
[34]
A. M. Houghton, P. A. Quintero, D. L. Perkins et al., “Elastin fragments drive disease progression in a murine model of emphysema,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 753–759, 2006.
[35]
S. Wright, C. Parham, B. Lee et al., “Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity,” Neurobiology of Aging. In press.
[36]
R. Al-Jamal and D. G. Harrison, “Tissue repair,” WO2005037313, 2003, http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_GB&FT=D&date=20050428&CC=WO&NR=2005037313A2&KC=A2.
[37]
R. O. Hynes, “Integrins: bidirectional, allosteric signaling machines,” Cell, vol. 110, no. 6, pp. 673–687, 2002.
[38]
S. J. Shattil, C. Kim, and M. H. Ginsberg, “The final steps of integrin activation: the end game,” Nature Reviews Molecular Cell Biology, vol. 11, no. 4, pp. 288–300, 2010.
[39]
R. Pankov, T. Markovska, R. Hazarosova, P. Antonov, L. Ivanova, and A. Momchilova, “Cholesterol distribution in plasma membranes of β1 integrin-expressing and β1 integrin-deficient fibroblasts,” Archives of Biochemistry and Biophysics, vol. 442, no. 2, pp. 160–168, 2005.
[40]
G. Pande, “The role of membrane lipids in regulation of integrin functions,” Current Opinion in Cell Biology, vol. 12, no. 5, pp. 569–574, 2000.
[41]
I. Petrache, V. Natarajan, L. Zhen et al., “Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice,” Nature Medicine, vol. 11, no. 5, pp. 491–498, 2005.
[42]
B. Butler, C. Gao, A. T. Mersich, and S. D. Blystone, “Purified integrin adhesion complexes exhibit actin-polymerization activity,” Current Biology, vol. 16, no. 3, pp. 242–251, 2006.
[43]
J. D. Whittard and S. K. Akiyama, “Activation of β1 integrins induces cell-cell adhesion,” Experimental Cell Research, vol. 263, no. 1, pp. 65–76, 2001.
[44]
N. Minematsu, A. Blumental-Perry, and S. D. Shapiro, “Cigarette smoke inhibits engulfment of apoptotic cells by macrophages through inhibition of actin rearrangement,” American Journal of Respiratory Cell and Molecular Biology, vol. 44, no. 4, pp. 474–482, 2011.
[45]
J. L. Daniel, I. R. Molish, L. Robkin, and H. Holmsen, “Nucleotide exchange between cytosolic ATP and F-actin-bound ADP may be a major energy-utilizing process in unstimulated platelets,” European Journal of Biochemistry, vol. 156, no. 3, pp. 677–684, 1986.
[46]
I. Bock-Marquette, A. Saxena, M. D. White, J. M. DiMaio, and D. Srivastava, “Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair,” Nature, vol. 432, no. 7016, pp. 466–472, 2004.
[47]
M. W. Johansson, S. R. Barthel, C. A. Swenson et al., “Eosinophil β1 integrin activation state correlates with asthma activity in a blind study of inhaled corticosteroid withdrawal,” Journal of Allergy and Clinical Immunology, vol. 117, no. 6, pp. 1502–1504, 2006.
[48]
R. Al-Jamal and D. J. Harrison, “Compounds and methods for the modulation of integrin function to mediate tissue repair,” WO2008104808, 2007, http://v3.espacenet.com/publicationDetails/biblio?DB=EPODOC&adjacent=true&locale=en_GB&FT=D&date=20080904&CC=WO&NR=2008104808A2&KC=A2.
[49]
E. C. Lucey, R. H. Goldstein, R. Breuer, B. N. Rexer, D. E. Ong, and G. L. Snider, “Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema,” Respiration, vol. 70, no. 2, pp. 200–205, 2003.
[50]
D. H. Miller, O. A. Khan, W. A. Sheremata et al., “A controlled trial of natalizumab for relapsing multiple sclerosis,” New England Journal of Medicine, vol. 348, no. 1, pp. 15–23, 2003.
