The Type I IFN Induction Pathway Constrains Th17-mediated Autoimmune Inflammation in Mice

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Apr 3

PMID 18382764

Citations 192

Authors

Beichu Guo

Elmer Y Chang

Genhong Cheng

Affiliations

Soon will be listed here.

Abstract

IFN-beta, a type I IFN, is widely used for the treatment of MS. However, the mechanisms behind its therapeutic efficacy are not well understood. Using a murine model of MS, EAE, we demonstrate that the Th17-mediated development of autoimmune disease is constrained by Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta-dependent (TRIF-dependent) type I IFN production and its downstream signaling pathway. Mice with defects in TRIF or type I IFN receptor (IFNAR) developed more severe EAE. Notably, these mice exhibited marked CNS inflammation, as manifested by increased IL-17 production. In addition, IFNAR-dependent signaling events were essential for negatively regulating Th17 development. Finally, IFN-beta-mediated IL-27 production by innate immune cells was critical for the immunoregulatory role of IFN-beta in the CNS autoimmune disease. Together, our findings not only may provide a molecular mechanism for the clinical benefits of IFN-beta in MS but also demonstrate a regulatory role for type I IFN induction and its downstream signaling pathways in limiting Th17 development and autoimmune inflammation.

Citing Articles

Bat genomes illuminate adaptations to viral tolerance and disease resistance.

Morales A, Dong Y, Brown T, Baid K, Kontopoulos D, Gonzalez V Nature. 2025; 638(8050):449-458.

PMID: 39880942 PMC: 11821529. DOI: 10.1038/s41586-024-08471-0.

Interaction between Th17 and central nervous system in multiple sclerosis.

Lai S, Wu X, Liu Y, Liu B, Wu H, Ma K Brain Behav Immun Health. 2025; 43():100928.

PMID: 39845807 PMC: 11751430. DOI: 10.1016/j.bbih.2024.100928.

RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis.

Wang Y, Ghimire S, Mangalam A, Kang Z bioRxiv. 2025; .

PMID: 39764033 PMC: 11703255. DOI: 10.1101/2024.12.24.630168.

Insights into ubiquitinome dynamics in the host‒pathogen interplay during Francisella novicida infection.

Yang L, Li Y, Xie Q, Xu T, Qi X Cell Commun Signal. 2024; 22(1):508.

PMID: 39425216 PMC: 11487746. DOI: 10.1186/s12964-024-01887-1.

[Two Cases of Behcet's Disease-Like Syndrome with Gene Deficiency in ].

Wang N, Xie Y, Wang Z Sichuan Da Xue Xue Bao Yi Xue Ban. 2024; 55(3):756-761.

PMID: 38948265 PMC: 11211776. DOI: 10.12182/20240560606.

References

Kastelein R, Hunter C, Cua D . Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007; 25:221-42. DOI: 10.1146/annurev.immunol.22.012703.104758. View

Le Page C, Genin P, Baines M, Hiscott J . Interferon activation and innate immunity. Rev Immunogenet. 2001; 2(3):374-86. View

Barton G, Medzhitov R . Toll-like receptor signaling pathways. Science. 2003; 300(5625):1524-5. DOI: 10.1126/science.1085536. View

Buttmann M, Rieckmann P . Interferon-beta1b in multiple sclerosis. Expert Rev Neurother. 2007; 7(3):227-39. DOI: 10.1586/14737175.7.3.227. View

Weaver C, Harrington L, Mangan P, Gavrieli M, Murphy K . Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006; 24(6):677-688. DOI: 10.1016/j.immuni.2006.06.002. View

Cousens L, Orange J, Su H, Biron C . Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proc Natl Acad Sci U S A. 1997; 94(2):634-9. PMC: 19565. DOI: 10.1073/pnas.94.2.634. View

Sonobe Y, Yawata I, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A . Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Res. 2005; 1040(1-2):202-7. DOI: 10.1016/j.brainres.2005.01.100. View

Stetson D, Medzhitov R . Type I interferons in host defense. Immunity. 2006; 25(3):373-81. DOI: 10.1016/j.immuni.2006.08.007. View

Awasthi A, Carrier Y, Peron J, Bettelli E, Kamanaka M, Flavell R . A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007; 8(12):1380-9. DOI: 10.1038/ni1541. View

10.

Hunter C . New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol. 2005; 5(7):521-31. DOI: 10.1038/nri1648. View

11.

Panitch H, Hirsch R, Haley A, Johnson K . Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet. 1987; 1(8538):893-5. DOI: 10.1016/s0140-6736(87)92863-7. View

12.

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

13.

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

14.

Lee S, Lee S . Toll-like receptors and inflammation in the CNS. Curr Drug Targets Inflamm Allergy. 2003; 1(2):181-91. DOI: 10.2174/1568010023344698. View

15.

Amadi-Obi A, Yu C, Liu X, Mahdi R, Clarke G, Nussenblatt R . TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007; 13(6):711-8. DOI: 10.1038/nm1585. View

16.

Gutcher I, Urich E, Wolter K, Prinz M, Becher B . Interleukin 18-independent engagement of interleukin 18 receptor-alpha is required for autoimmune inflammation. Nat Immunol. 2006; 7(9):946-53. DOI: 10.1038/ni1377. View

17.

Agrawal S, Yong V . Immunopathogenesis of multiple sclerosis. Int Rev Neurobiol. 2007; 79:99-126. DOI: 10.1016/S0074-7742(07)79005-0. View

18.

Takeda K, Kaisho T, Akira S . Toll-like receptors. Annu Rev Immunol. 2003; 21:335-76. DOI: 10.1146/annurev.immunol.21.120601.141126. View

19.

Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6(11):1133-41. PMC: 1618871. DOI: 10.1038/ni1261. View

20.

Fitzgerald D, Ciric B, Touil T, Harle H, Grammatikopolou J, Das Sarma J . Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007; 179(5):3268-75. DOI: 10.4049/jimmunol.179.5.3268. View