Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females

被引:5
作者
Cordeiro, Brendan [1 ,7 ]
Ahn, Jeeyoon Jennifer [2 ,14 ]
Gawde, Saurabh [3 ,4 ,7 ]
Ucciferri, Carmen [2 ,7 ]
Alvarez-Sanchez, Nuria [1 ,7 ]
Revelo, Xavier S. [5 ,7 ]
Stickle, Natalie [6 ,7 ]
Massey, Kaylea [3 ,7 ]
Brooks, David G. [2 ,5 ,7 ]
Guthridge, Joel M. [3 ,7 ,8 ]
Pardo, Gabriel [3 ,6 ,7 ,8 ]
Winer, Daniel A. [2 ,9 ,12 ,13 ]
Axtell, Robert C. [3 ,4 ,7 ]
Dunn, Shannon E. [2 ,10 ,11 ]
机构
[1] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON M5B 1W8, Canada
[2] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada
[3] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, Oklahoma City, OK 73104 USA
[4] Oklahoma Univ, Dept Microbiol & Immunol, Hlth Sci Ctr, Oklahoma City, OK 73104 USA
[5] Univ Minnesota, Dept Integrat Biol & Physiol, Minneapolis, MN 55455 USA
[6] Univ Hlth Network, Bioinformat & High Performance Comp Core, Toronto, ON M5G 1L7, Canada
[7] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2C4, Canada
[8] Oklahoma Med Res Fdn, Multiple Sclerosis Ctr Excellence, Oklahoma City, OK 73104 USA
[9] Buck Inst Res Aging, Novato, CA 94945 USA
[10] Womens Coll Hosp, Womens Coll Res Inst, Toronto, ON M5G 1N8, Canada
[11] Sunnybrook Med Ctr, Sunnybrook Res Inst, Toronto, ON M4M 3M5, Canada
[12] Univ Hlth Network, Toronto Gen Hosp Res Inst, Div Cellular & Mol Biol, Diabet Res Grp, Toronto, ON M5G 1L7, Canada
[13] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada
[14] Bristol Myers Squibb, Cambridge, MA 02141 USA
基金
加拿大健康研究院; 美国国家卫生研究院;
关键词
MULTIPLE-SCLEROSIS; IFN-GAMMA; T-CELLS; CUTTING EDGE; STAT4; ACTIVATION; GENE-EXPRESSION; ALPHA; TH1; IL-12; BET;
D O I
10.1016/j.cmet.2024.07.017
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-alpha and potentiated STAT1 expression and IFN-gamma production by naive CD4(+) T cells uniquely in female mice. This T cell phenotype was driven by increased adiposity and was prevented by the removal of ovaries or knockdown of the type I IFN receptor in T cells. Our findings offer a mechanistic explanation of how obesity enhances autoimmunity.
引用
收藏
页码:2298 / 2314.e11
页数:29
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