IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis
| Autor: | Heather J. Faust, Matthew T. Wolf, Hong Zhang, Judith Campisi, Drew M. Pardoll, Kaitlyn Sadtler, Clifton O. Bingham, Liam Chung, David R. Maestas, Franck Housseau, Daohong Zhou, Ada J. Tam, Jennifer H. Elisseeff, Jin Han, Ok-Hee Jeon, Alexis N. Peña |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence Male Aging Arthritis Biology Adaptive Immunity Regenerative Medicine Pathogenesis 03 medical and health sciences Mice 0302 clinical medicine Immune system Osteoarthritis medicine Animals Humans Cellular Senescence Mice Knockout Innate lymphoid cell Interleukin-17 Wnt signaling pathway General Medicine medicine.disease Arthritis Experimental Immunity Innate Receptors Interleukin-4 Mice Inbred C57BL Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Th17 Cells Interleukin 17 Antibody Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16(INK4a) (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ(+) T cells, and CD4(+) T cells contributed to IL-17 expression. Intra-articular injection of IL-17–neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment. |
| Databáze: | OpenAIRE |
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