A Possible Physiological Role of Caspase-11 During Germinal Center Reaction

  • Published : 2008.09.30

Abstract

Caspase-11 has been known as a dual regulator of cytokine maturation and apoptosis. Although the role of caspase-11 under pathological conditions has been well documented, its physiological role has not been studied much. In the present study, we investigated a possible physiological function of caspase-11 during immune response. In the absence of caspase-11, immunized spleen displayed increased cellularity and abnormal germinal center structure with disrupted microarchitecture. The rate of cell proliferation and apoptosis in the immunized spleen was not changed in the caspase-11-deficient mice. Furthermore, the caspase-11-deficient peritoneal macrophages showed normal phagocytotic activity. However, caspase-11-/-splenocytes and macrophages showed defective migrating capacity. The dysregulation of cell migration did not seem to be mediated by caspase-3, interleukin-$1{\alpha}$ or interleukin-$1{\beta}$ which acts downstream of caspase-11. These results suggest that a direct regulation of immune cell migration by caspase-11 is critical for the formation of germinal center microarchitecture during immune response. However, humoral immunity in the caspase-11-deficient mice was normal, suggesting the formation of germinal center structure is not essential for the affinity maturation of the antibodies.

References

  1. Antonopoulos C, Cumberbatch M, Dearman RJ, Daniel RJ, Kimber I, and Groves RW (2001) Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice. J Immunol 166: 3672-3677. https://doi.org/10.4049/jimmunol.166.6.3672
  2. Alimzhanov MB, Kuprash DV, Kosco-Vilbois MH, Luz A, Turetskaya RL, Tarakhovsky A, Rajewsky K, Nedospasov SA, and Pfeffer K (1997) Abnormal development of secondary lymphoid tissues in lymphotoxin beta- deficient mice. Proc Natl Acad Sci USA 94: 9302-9307.
  3. Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, Kuklin NA, Bouley DM, Thomas J, Kanangat S, and Mucenski ML (1995) Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol 155: 1685-1693.
  4. Cook MC, Korner H, Riminton DS, Lemckert FA, Hasbold J, Amesbury M, Hodgkin PD, Cyster JG, Sedgwick JD, and Basten A (1998) Generation of splenic follicular structure and B cell movement in tumor necrosis factor-deficient mice. J Exp Med 188: 1503-1510. https://doi.org/10.1084/jem.188.8.1503
  5. Cumberbatch M, Dearman RJ, Antonopoulos C, Groves RW, and Kimber I (2001) Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-betadependent mechanism. Immunology 102: 323-330. https://doi.org/10.1046/j.1365-2567.2001.01187.x
  6. De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, and Strauss-Schoenberger J (1994) Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264: 703-707. https://doi.org/10.1126/science.8171322
  7. Furuya T, Hayakawa H, Yamada M, Yoshimi K, Hisahara S, Miura M, Mizuno Y, and Mochizuki H (2004) Caspase-11 mediates inflammatory dopaminergic cell death in the 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. J Neurosci 24: 1865-1872. https://doi.org/10.1523/JNEUROSCI.3309-03.2004
  8. Hisahara S, Yuan J, Momoi T, Okano H, and Miura M (2001) Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination. J Exp Med 193: 111-122. https://doi.org/10.1084/jem.193.1.111
  9. Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, and Yuan J (2000) Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol 149: 613-622. https://doi.org/10.1083/jcb.149.3.613
  10. Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T, and Kikutani H (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1: 167-178. https://doi.org/10.1016/1074-7613(94)90095-7
  11. Kuida K, Haydar TF, Kuan C-U, Gu Y, Taya C, Karasuyama H, Su MSS, Rakic P, and Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase-9. Cell 94: 325-337. https://doi.org/10.1016/S0092-8674(00)81476-2
  12. Le Hir M, Bluethmann H, Kosco-Vilbois MH, Muller M, Di Padova F, Moore M, Ryffel B, and Eugster HP (1996) Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling. J Exp Med 183: 2367-2372. https://doi.org/10.1084/jem.183.5.2367
  13. Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, von Andrian UH, Mitchison T, and Yuan J (2007) Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat Cell Biol 9: 276-286. https://doi.org/10.1038/ncb1541
  14. Mackay CR (2001) Chemokines: immunology's high impact factors. Nat Immunol 2: 95-101. https://doi.org/10.1038/84298
  15. Matsumoto M, Lo SF, Carruthers CJ, Min J, Mariathasan S, Huang G, Plas DR, Martin SM, Geha RS, Nahm MH, and Chaplin DD (1996) Affinity maturation without germinal centres in lymphotoxin-alphadeficient mice. Nature 382: 462- 466. https://doi.org/10.1038/382462a0
  16. Moser B, and Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2: 123-128. https://doi.org/10.1038/84219
  17. Tarlinton DM, and Smith KG (2000) Dissecting affinity maturation: a model explaining selection of antibody-forming cells and memory B cells in the germinal centre. Immunol Today 21: 436-441. https://doi.org/10.1016/S0167-5699(00)01687-X
  18. Pasparakis M, Alexopoulou L, Episkopou V, and Kollias G (1996) Immune and inflammatory responses in TNF alphadeficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184: 1397-1411. https://doi.org/10.1084/jem.184.4.1397
  19. Pasparakis M, Alexopoulou L, Grell M, Pfizenmaier K, Bluethmann H and Kollias G (1997) Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor. Proc Natl Acad Sci USA 94: 6319-6323.
  20. Wang S, Miura M, Jung YK, Zhu H, Gagliardini V, Shi L, Greenberg AH, and Yuan J (1996) Identification and characterization of Ich-3, a member of the interleukin-1beta converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J Biol Chem 271: 20580-20587. https://doi.org/10.1074/jbc.271.34.20580
  21. Wang S, Miura M, Jung YK, Zhu H, Li E, and Yuan J (1998) Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92: 501-509. https://doi.org/10.1016/S0092-8674(00)80943-5