IL-11 Regulates Autoimmune Demyelination

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2009 Sep 8

PMID 19734214

Citations 36

Authors

Blake T Gurfein

Yueting Zhang

Carolina B Lopez

Azeb Tadesse Argaw

Andleeb Zameer

Thomas M Moran

Gareth R John

Affiliations

Soon will be listed here.

Abstract

Current therapies for the autoimmune demyelinating disease multiple sclerosis (MS) target inflammation, but do not directly address neuroprotection or lesion repair. Cytokines of the gp130 family regulate survival and differentiation of both neural and immune cells, and we recently identified expression of the family member IL-11 in active MS plaques. In this study, we show that IL-11 regulates the clinical course and neuropathology of experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of MS. Importantly, the effects of IL-11 are achieved via a combination of immunoregulation and direct neuroprotection. IL-11R-alpha-null (IL-11Ralpha(-/-)) mice displayed a significant increase in clinical severity and neuropathology of experimental autoimmune encephalomyelitis compared with wild-type littermates. Inflammation, demyelination, and oligodendrocyte and neuronal loss were all exacerbated in IL-11Ra(-/-) animals. Conversely, wild-type mice treated with IL-11 displayed milder clinical signs and neuropathology than vehicle-treated controls. In cocultures of murine myelin oligodendrocyte glycoprotein(35-55)-specific CD4+ T lymphocytes and CD11c+ APCs, IL-11 treatment resulted in a significant decrease in T cell-derived effector cytokine production. This effect was generated via modulation of CD11c+ APC-mediated lymphocyte activation, and was associated with a decrease in the size of the CD11c+ cell population. Conversely, IL-11 strongly reduced apoptosis and potentiated mitosis in primary cultures of mouse oligodendrocyte progenitors. Collectively, these data reveal that IL-11 regulates inflammatory demyelination via a unique combination of immunoregulation and neuroprotection. IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.

Citing Articles

Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.

McInnis J, Sood D, Guo L, Dufault M, Garcia M, Passaro R Commun Biol. 2024; 7(1):1597.

PMID: 39616264 PMC: 11608238. DOI: 10.1038/s42003-024-07231-0.

Astrocytic DLL4-NOTCH1 signaling pathway promotes neuroinflammation via the IL-6-STAT3 axis.

Mora P, Laisne M, Bourguignon C, Rouault P, Jaspard-Vinassa B, Maitre M J Neuroinflammation. 2024; 21(1):258.

PMID: 39390606 PMC: 11468415. DOI: 10.1186/s12974-024-03246-w.

Understanding interleukin 11 as a disease gene and therapeutic target.

Cook S Biochem J. 2023; 480(23):1987-2008.

PMID: 38054591 PMC: 10754292. DOI: 10.1042/BCJ20220160.

Interleukin-11 in Pathologies of the Nervous System.

Airapetov M, Eresko S, Ignatova P, Lebedev A, Bychkov E, Shabanov P Mol Biol. 2023; 57(1):1-6.

PMID: 37016665 PMC: 10062686. DOI: 10.1134/S0026893323010028.

Neuroinflammatory Profiling in SIV-Infected Chinese-Origin Rhesus Macaques on Antiretroviral Therapy.

Solis-Leal A, Siddiqui S, Wu F, Mohan M, Hu W, Doyle-Meyers L Viruses. 2022; 14(1).

PMID: 35062343 PMC: 8781366. DOI: 10.3390/v14010139.

References

Di Marco R, Khademi M, Wallstrom E, Iacobaeus E, Salvaggio A, Caracappa S . Curative effects of recombinant human Interleukin-6 in DA rats with protracted relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 2001; 116(2):168-77. DOI: 10.1016/s0165-5728(01)00301-0. View

Paul S, Bennett F, Calvetti J, Kelleher K, Wood C, OHara Jr R . Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci U S A. 1990; 87(19):7512-6. PMC: 54777. DOI: 10.1073/pnas.87.19.7512. View

Bruck W, Stadelmann C . The spectrum of multiple sclerosis: new lessons from pathology. Curr Opin Neurol. 2005; 18(3):221-4. DOI: 10.1097/01.wco.0000169736.60922.20. View

Samoilova E, Horton J, Hilliard B, Liu T, Chen Y . IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol. 1998; 161(12):6480-6. View

Caporaso G, Chao M . Telomerase and oligodendrocyte differentiation. J Neurobiol. 2001; 49(3):224-34. DOI: 10.1002/neu.1077. View

Robb L, Li R, Hartley L, Nandurkar H, Koentgen F, Begley C . Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med. 1998; 4(3):303-8. DOI: 10.1038/nm0398-303. View

Musashi M, Yang Y, Paul S, Clark S, Sudo T, Ogawa M . Direct and synergistic effects of interleukin 11 on murine hemopoiesis in culture. Proc Natl Acad Sci U S A. 1991; 88(3):765-9. PMC: 50894. DOI: 10.1073/pnas.88.3.765. View

Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S . IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006; 177(1):566-73. DOI: 10.4049/jimmunol.177.1.566. View

John G, Shankar S, Shafit-Zagardo B, Massimi A, Lee S, Raine C . Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med. 2002; 8(10):1115-21. DOI: 10.1038/nm781. View

10.

Keegan B, Noseworthy J . Multiple sclerosis. Annu Rev Med. 2002; 53:285-302. DOI: 10.1146/annurev.med.53.082901.103909. View

11.

Ridet J, Malhotra S, Privat A, Gage F . Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1998; 20(12):570-7. DOI: 10.1016/s0166-2236(97)01139-9. View

12.

Chen L, Brosnan C . Exacerbation of experimental autoimmune encephalomyelitis in P2X7R-/- mice: evidence for loss of apoptotic activity in lymphocytes. J Immunol. 2006; 176(5):3115-26. DOI: 10.4049/jimmunol.176.5.3115. View

13.

Steinman L . Nuanced roles of cytokines in three major human brain disorders. J Clin Invest. 2008; 118(11):3557-63. PMC: 2575716. DOI: 10.1172/JCI36532. View

14.

Linthicum D, Munoz J, Blaskett A . Acute experimental autoimmune encephalomyelitis in mice. I. Adjuvant action of Bordetella pertussis is due to vasoactive amine sensitization and increased vascular permeability of the central nervous system. Cell Immunol. 1982; 73(2):299-310. DOI: 10.1016/0008-8749(82)90457-9. View

15.

Argaw A, Zhang Y, Snyder B, Zhao M, Kopp N, Lee S . IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol. 2006; 177(8):5574-84. DOI: 10.4049/jimmunol.177.8.5574. View

16.

Trepicchio W, Wang L, BOZZA M, Dorner A . IL-11 regulates macrophage effector function through the inhibition of nuclear factor-kappaB. J Immunol. 1998; 159(11):5661-70. View

17.

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

18.

Nandurkar H, Robb L, Tarlinton D, Barnett L, Kontgen F, Begley C . Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis. Blood. 1997; 90(6):2148-59. View

19.

Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2):179-89. DOI: 10.1016/j.immuni.2006.01.001. View

20.

Hauser S, Oksenberg J . The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006; 52(1):61-76. DOI: 10.1016/j.neuron.2006.09.011. View