IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis

Heather J. Faust, Hong Zhang, Jin Han, Matthew T. Wolf, Ok Hee Jeon, Kaitlyn Sadtler, Alexis N. Peña, Liam Chung, David R. Maestas, Ada J. Tam, Drew M. Pardoll, Judith Campisi, Franck Housseau, Daohong Zhou, Clifton O. Bingham, Jennifer H. Elisseeff

Resultado de la investigación: Articlerevisión exhaustiva

57 Citas (Scopus)

Resumen

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 p16INK4a (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.

Idioma originalEnglish (US)
Páginas (desde-hasta)5493-5507
Número de páginas15
PublicaciónJournal of Clinical Investigation
Volumen130
N.º10
DOI
EstadoPublished - oct. 1 2020
Publicado de forma externa

ASJC Scopus subject areas

  • Medicine(all)

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