A hallmark of aging-related organ deterioration is a dysregulated immune response characterized by pathologic leukocyte infiltration of affected tissues. Mechanisms and genes involved are as yet unknown. To identify genes associated with aging-related renal infiltration, we analyzed kidneys from aged mice (≥20 strains) for infiltrating leukocytes followed by Haplotype Association Mapping (HAM) analysis. Immunohistochemistry revealed CD45+ cell clusters (predominantly T and B cells) in perivascular areas coinciding with PNAd+ high endothelial venules and podoplanin+ lymph vessels indicative of tertiary lymphoid organs. Cumulative cluster size increased with age (analyzed at 6, 12 and 20 months). Based on the presence or absence of clusters in male and female mice at 20 months, HAM analysis revealed significant associations with loci on Chr1, Chr2, Chr8 and Chr14 in male mice, and with loci on Chr4, Chr7, Chr13 and Chr14 in female mice. Wisp2 (Chr2) showed the strongest association (P = 5.00×10？137) in male mice; Ctnnbip1 (P = 6.42×10？267) and Tnfrsf8 (P = 5.42×10？245) (both on Chr4) showed the strongest association in female mice. Both Wisp2 and Ctnnbip1 are part of the Wnt-signaling pathway and the encoded proteins were expressed within the tertiary lymphoid organs. In conclusion, this study revealed differential lymphocytic infiltration and tertiary lymphoid organ formation in aged mouse kidneys across different inbred mouse strains. HAM analysis identified candidate genes involved in the Wnt-signaling pathway that may be causally linked to tertiary lymphoid organ formation.
References
[1]
Hoang K, Tan JC, Derby G, Blouch KL, Masek M, et al. (2003) Determinants of glomerular hypofiltration in aging humans. Kidney Int 64: 1417–1424. doi: 10.1046/j.1523-1755.2003.00207.x
[2]
Choudhury D, Levi M (2011) Kidney aging—inevitable or preventable? Nat Rev Nephrol 7: 706–717. doi: 10.1038/nrneph.2011.104
[3]
Lindeman RD, Tobin J, Shock NW (1985) Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33: 278–285.
[4]
Melk A, Mansfield ES, Hsieh SC, Hernandez-Boussard T, Grimm P, et al. (2005) Transcriptional analysis of the molecular basis of human kidney aging using cDNA microarray profiling. Kidney Int 68: 2667–2679. doi: 10.1111/j.1523-1755.2005.00738.x
[5]
Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, et al. (2010) Acute kidney injury: A springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 298: F1078–94. doi: 10.1152/ajprenal.00017.2010
[6]
Rodwell GE, Sonu R, Zahn JM, Lund J, Wilhelmy J, et al. (2004) A transcriptional profile of aging in the human kidney. PLoS Biol 2: e427. doi: 10.1371/journal.pbio.0020427
[7]
Brink TC, Regenbrecht C, Demetrius L, Lehrach H, Adjaye J (2009) Activation of the immune response is a key feature of aging in mice. Biogerontology 10: 721–734. doi: 10.1007/s10522-009-9219-1
[8]
Tullius SG, Milford E (2011) Kidney allocation and the aging immune response. N Engl J Med 364: 1369–1370. doi: 10.1056/nejmc1103007
[9]
Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: From ontogeny to neogenesis. Nat Immunol 7: 344–353. doi: 10.1038/ni1330
[10]
Kelly FM, Reddy RN, Roberts BR, Gangappa S, Williams IR, et al. (2009) TGF-beta upregulation drives tertiary lymphoid organ formation and kidney dysfunction in calcineurin A-alpha heterozygous mice. Am J Physiol Renal Physiol 296: F512–20. doi: 10.1152/ajprenal.90629.2008
[11]
Tsaih SW, Korstanje R (2009) Haplotype association mapping in mice. Methods Mol Biol 573: 213–222. doi: 10.1007/978-1-60761-247-6_12
[12]
Sinke AP, Caputo C, Tsaih SW, Yuan R, Ren D, et al. (2011) Genetic analysis of mouse strains with variable serum sodium concentrations identifies the nalcn sodium channel as a novel player in osmoregulation. Physiol Genomics 43: 265–270. doi: 10.1152/physiolgenomics.00188.2010
[13]
Tsaih SW, Pezzolesi MG, Yuan R, Warram JH, Krolewski AS, et al. (2010) Genetic analysis of albuminuria in aging mice and concordance with loci for human diabetic nephropathy found in a genome-wide association scan. Kidney Int 77: 201–210. doi: 10.1038/ki.2009.434
[14]
Kang HM, Zaitlen NA, Wade CM, Kirby A, Heckerman D, et al. (2008) Efficient control of population structure in model organism association mapping. Genetics 178: 1709–1723. doi: 10.1534/genetics.107.080101
[15]
Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6: 205–217. doi: 10.1038/nri1786
[16]
Mounzer RH, Svendsen OS, Baluk P, Bergman CM, Padera TP, et al. (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116: 2173–2182. doi: 10.1182/blood-2009-12-256065
[17]
Pabst R (2007) Plasticity and heterogeneity of lymphoid organs. what are the criteria to call a lymphoid organ primary, secondary or tertiary? Immunol Lett 112: 1–8.
[18]
Matsui K, Nagy-Bojarsky K, Laakkonen P, Krieger S, Mechtler K, et al. (2003) Lymphatic microvessels in the rat remnant kidney model of renal fibrosis: Aminopeptidase p and podoplanin are discriminatory markers for endothelial cells of blood and lymphatic vessels. J Am Soc Nephrol 14: 1981–1989. doi: 10.1097/01.asn.0000076078.50889.43
[19]
Lee AS, Lee JE, Jung YJ, Kim DH, Kang KP, et al. (2013) Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. Kidney Int 83: 50–62. doi: 10.1038/ki.2012.312
[20]
Hjelmstrom P (2001) Lymphoid neogenesis: De novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol 69: 331–339.
[21]
Thaunat O, Field AC, Dai J, Louedec L, Patey N, et al. (2005) Lymphoid neogenesis in chronic rejection: Evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A 102: 14723–14728. doi: 10.1073/pnas.0507223102
[22]
Watanabe Y, Itoh Y, Yoshida F, Koh N, Tamai H, et al. (1991) Unique glomerular lesion with spontaneous lipid deposition in glomerular capillary lumina in the NON strain of mice. Nephron 58: 210–218. doi: 10.1159/000186417
[23]
van Goor H, Leuvenink HG (2009) The goddess of the waters. Kidney Int 75: 767–769. doi: 10.1038/ki.2009.45
[24]
Thaunat O, Kerjaschki D, Nicoletti A (2006) Is defective lymphatic drainage a trigger for lymphoid neogenesis? Trends Immunol 27: 441–445. doi: 10.1016/j.it.2006.08.003
[25]
Nasr IW, Reel M, Oberbarnscheidt MH, Mounzer RH, Baddoura FK, et al. (2007) Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transplant 7: 1071–1079. doi: 10.1111/j.1600-6143.2007.01756.x
[26]
Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, et al. (2010) Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol 185: 717–728. doi: 10.4049/jimmunol.0903589
[27]
Carragher DM, Rangel-Moreno J, Randall TD (2008) Ectopic lymphoid tissues and local immunity. Semin Immunol 20: 26–42. doi: 10.1016/j.smim.2007.12.004
[28]
Pablos JL, Santiago B, Tsay D, Singer MS, Palao G, et al. (2005) A HEV-restricted sulfotransferase is expressed in rheumatoid arthritis synovium and is induced by lymphotoxin-alpha/beta and TNF-alpha in cultured endothelial cells. BMC Immunol 6: 6.
[29]
Salomonsson S, Larsson P, Tengner P, Mellquist E, Hjelmstrom P, et al. (2002) Expression of the B cell-attracting chemokine CXCL13 in the target organ and autoantibody production in ectopic lymphoid tissue in the chronic inflammatory disease sjogren's syndrome. Scand J Immunol 55: 336–342. doi: 10.1046/j.1365-3083.2002.01058.x
[30]
Segerer S, Schlondorff D (2008) B cells and tertiary lymphoid organs in renal inflammation. Kidney Int 73: 533–537. doi: 10.1038/sj.ki.5002734
[31]
Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, et al. (1982) Production of a monoclonal antibody specific for hodgkin and sternberg-reed cells of hodgkin's disease and a subset of normal lymphoid cells. Nature 299: 65–67. doi: 10.1038/299065a0
[32]
Holbourn KP, Acharya KR, Perbal B (2008) The CCN family of proteins: Structure-function relationships. Trends Biochem Sci 33: 461–473. doi: 10.1016/j.tibs.2008.07.006
[33]
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, et al. (1998) WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A 95: 14717–14722. doi: 10.1073/pnas.95.25.14717
[34]
Liu J, Ding X, Tang J, Cao Y, Hu P, et al. (2011) Enhancement of canonical Wnt/beta-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One 6: e27496. doi: 10.1371/journal.pone.0027496
[35]
Zhang JL, Huang Y, Qiu LY, Nickel J, Sebald W (2007) Von willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms. J Biol Chem 282: 20002–20014. doi: 10.1074/jbc.m700456200
[36]
Tago K, Nakamura T, Nishita M, Hyodo J, Nagai S, et al. (2000) Inhibition of wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev 14: 1741–1749.
[37]
Smith CA, Gruss HJ, Davis T, Anderson D, Farrah T, et al. (1993) CD30 antigen, a marker for hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell 73: 1349–1360. doi: 10.1016/0092-8674(93)90361-s
[38]
Horie R, Watanabe T (1998) CD30: Expression and function in health and disease. Semin Immunol 10: 457–470. doi: 10.1006/smim.1998.0156
[39]
Gaspal F, Withers D, Saini M, Bekiaris V, McConnell FM, et al. (2011) Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice. J Exp Med 208: 1579–1584. doi: 10.1084/jem.20101484
[40]
Bowen MA, Lee RK, Miragliotta G, Nam SY, Podack ER (1996) Structure and expression of murine CD30 and its role in cytokine production. J Immunol 156: 442–449.
[41]
Martin JE, Sheaff MT (2007) Renal ageing. J Pathol 211: 198–205. doi: 10.1002/path.2111
