Abstract
Sparc-null mice have been used as models to assess tumor-host immune cell interactions. However, it is not known if they have a competent immune system. In this study, the immune systems of Sparc wild-type and null mice were compared. Mice were assessed for differences in total body weight, spleen weight and spleen-to-body weight ratios. Spleens were compared with respect to morphology, and Sparc, Ki-67, MOMA-1 and IgM expression. Immune cells in blood, bone marrow and spleen were assessed by blood smears, automated blood panel, and flow cytometry. Additionally, the ability of Sparc-null mice to respond to immune challenge was evaluated using a footpad model. The morphological and immunohistochemical results indicated that Sparc-null spleens had more white pulp, hyperproliferative B cells in the germinal centers, and decreased marginal zones. Sparc-null spleens lacked normal Sparc expression in red and white pulp, marginal zones, endothelial and sinusoidal cells. By flow analysis, B cells were decreased and T cells were increased in the bone marrow. Finally, Sparc-null mice were unable to mount an immune response following footpad lipopolysaccharide challenge. These data confirm that Sparc-null mice have an impaired immune system.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gilmour DT, Lyon GJ, Carlton MB, Sanes JR, Cunningham JM, Anderson JR et al. Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens. EMBO J 1998; 17: 1860ā1870.
Norose K, Clark JI, Syed NA, Basu A, Heber-Katz E, Sage EH et al. SPARC deficiency leads to early-onset cataractogenesis. Invest Ophthalmol Vis Sci 1998; 39: 2674ā2680.
Delany AM, Kalajzic I, Bradshaw AD, Sage EH, Canalis E . Osteonectin-null mutation compromises osteoblast formation, maturation, and survival. Endocrinology 2003; 144: 2588ā2596.
Bradshaw AD, Graves DC, Motamed K, Sage EH . SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proc Natl Acad Sci USA 2003; 100: 6045ā6050.
Bradshaw AD, Reed MJ, Sage EH . SPARC-null mice exhibit accelerated cutaneous wound closure. J Histochem Cytochem 2002; 50: 1ā10. Erratum in: J Histochem Cytochem 2002; 50: 875.
Puolakkainen PA, Brekken RA, Muneer S, Sage EH . Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res 2004; 2: 215ā224.
Bos TJ, Cohn SL, Kleinman HK, Murphy-Ulrich JE, Podhajcer OL, Rempel SA et al. International Hermelin brain tumor symposium on matricellular proteins in normal and cancer cell-matrix interactions. Matrix Biol 2004; 23: 63ā69.
Mok SC, Chan WY, Wong KK, Cheung KK, Lav CC, Ng SW et al. SPARC, an extracellular matrix protein with tumor-suppressing activity in human ovarian epithelial cells. Oncogene 1996; 12: 1895ā1901.
Said N, Motamed K . Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis. Am J Pathol 2005; 167: 1739ā1752.
Yiu GK, Chan WY, Ng SW, Chan PS, Cheung KK, Berkowitz RS et al. SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. Am J Pathol 2001; 159: 609ā622.
Chlenski A, Liu S, Crawford SE, Volpert OV, DeVries GH, Evangelista A et al. SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res 2002; 62: 7357ā7363.
Chlenski A, Liu S, Baker LJ, Yang Q, Tian Y, Salwen HR et al. Neuroblastoma angiogenesis is inhibited with a folded synthetic molecule corresponding to the epidermal growth factor-like module of the follistatin domain of SPARC. Cancer Res 2004; 64: 7420ā7425.
Ledda F, Bravo AI, Adris S, Bover L, Mordoh J, Podhajcer OL . The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. J Invest Dermatol 1997a; 108: 210ā214.
Rempel SA, Golembieski WA, Ge S, Lemke N, Elisevich K, Mikkelsen T et al. SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas. J Neuropathol Exp Neurol 1998; 57: 1112ā1121.
Ledda MF, Adris S, Bravo AI, Kairiyama C, Bover L, Chernajovsky Y et al. Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells. Nat Med 1997a; 3: 171ā176.
Golembieski WA, Ge S, Nelson K, Mikkelsen T, Rempel SA . Increased SPARC expression promotes U87 glioblastoma invasion in vitro. Int J Dev Neurosci 1999; 17: 463ā472.
Schultz C, Lemke N, Ge S, Golembieski WA, Rempel SA . Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo. Cancer Res 2002; 62: 6270ā6277.
Sangaletti S, Stoppacciaro A, Guiducci C, Torrisi MR, Columbo MP . Leukocyte, rather than tumor-produced SPARC, determines stroma and collagen type IV deposition in mammary carcinoma. J Exp Med 2003; 98: 1475ā1485.
Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH . Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 2003; 111: 487ā495.
Puolakkainen PA, Brekken RA, Muneer S, Sage EH . Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res 2004; 2: 215ā224.
Alvarez MJ, Prada F, Salvatierra E, Bravo AI, Lutzky VP, Carbone C et al. Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity. Cancer Res 2005; 65: 5123ā5132.
Savani RC, Zhou Z, Arguiri E, Wang S, Vu D, Howe CC et al. Bleomycin-induced pulmonary injury in mice deficient in SPARC. Am J Physiol Lung Cell Mol Physiol 2000; 279: L743āL750.
Sangaletti S, Gioiosa L, Guiducci C, Rotta G, Rescigno M, Stoppacciaro A et al. Accelerated dendritic-cell migration and T-cell priming in SPARC-deficient mice. J Cell Science 2005; 118: 3685ā3694.
Aycock RL, Bradshaw AC, Sage EH, Starcher B . Development of UV-induced squamous cell carcinomas is suppressed in the absence of SPARC. J Invest Dermatol 2004; 123: 592ā599.
Sage EH, Vernon RB, Decker J, Funk S, Iruela-Arispe ML . Distribution of the calcium-binding protein SPARC in tissues of embryonic and adult mice. J Histochem Cytochem 1989; 37: 819ā829.
Shen Y, Iqbal J, Xiao L, Lynch RC, Rosenwald A, Staudt LM et al. Distinct gene expression profiles in different B-cell compartments in human peripheral lymphoid organs. BMC Immunol 2004; 5: 20.
Kzhyshkowska J, Gratchev A, Goerdt S . Stabilin-1, a homeostatic scavenger receptor with multiple functions. J Cell Mol Med 2006; 10: 635ā649.
Kzhyshkowska J, Workman G, Cardo-Vila M, Arap W, Pasqualini R, Gratchev A et al. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol 2006; 176: 5825ā5832.
Kelly KA, Allport JR, Yu AM, Sinh S, Sage EH, Gerszten RE et al. SPARC is a VCAM-1 counter-ligand that mediates leukocyte transmigration. J Leukoc Biol December 18 (E-pub ahead of print).
Pillai S, Cariappa A, Moran ST . Marginal zone B cells. Ann Rev Immunol 2005; 23: 161ā196.
Lopes-Carvalho T, Kearney JF . Development and selection of marginal zone B cells. Immunol Rev 2004; 197: 192ā205.
Cariappa A, Tang M, Parng C, Nebelitskiy E, Carroll M, Georgopoulos K et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 2001; 14: 603ā615.
Guinamard R, Okigaki M, Schlesinger J, Ravetch JV . Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nature Immunol 2000; 1: 31ā36.
Bradshaw AD, Sage EH . SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J Clin Invest 2001; 107: 1049ā1054.
Oritani K, Kincade PW . Identification of stromal cell products that interact with pre-B cells. J Cell Biol 1996; 134: 771ā782.
Stary M, Pasteiner W, Summer A, Hrdina A, Eger A, Weitzer G et al. Parietal endoderm secreted SPARC promotes early cardiomyogenesis in vitro. Exp Cell Res 2005; 310: 331ā343.
Ishimoto H, Ginzinger DG, Matsumoto T, Hattori Y, Furuya M, Minegishi K et al. Differential zonal expression and adrenocorticotropin regulation of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, in the midgestation human fetal adrenal gland: implications for adrenal development. J Clin Endocrin Metab 2003; 91: 3208ā3214.
Chi DS, Harris NS . A simple method for the isolation of murine peripheral blood lymphocytes. J Immunol Methods 1978; 19: 169ā172.
Acknowledgements
We are grateful to Dr Chin Howe for the Sparc-null mice. We thank Dr Hynda K Kleinman for her thoughtful discussion. This work was supported in part by the NIH/NCI Grant CA086997 (SAR). We are grateful for the continued support of the Barbara Jane Levy and the Gayle Halperin Kahn Funds.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rempel, S., Hawley, R., GutiĆ©rrez, J. et al. Splenic and immune alterations of the Sparc-null mouse accompany a lack of immune response. Genes Immun 8, 262ā274 (2007). https://doi.org/10.1038/sj.gene.6364388
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gene.6364388
Keywords
This article is cited by
-
Stromal expression of SPARC in pancreatic adenocarcinoma
Cancer and Metastasis Reviews (2013)
-
Thrombospondin-2 and SPARC/osteonectin are critical regulators of bone remodeling
Journal of Cell Communication and Signaling (2009)
-
The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host
Cancer and Metastasis Reviews (2008)
-
The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host
Cancer and Metastasis Reviews (2008)