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

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

Abstract

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.

Authors

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

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Figure 4

IL-4 is required for wound healing after SnC clearance and IL-17 reduction.

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IL-4 is required for wound healing after SnC clearance and IL-17 reducti...
(A) Quantification of Il4 mRNA expression in articular joints of young and aged mice (no surgery, sham surgery, after ACLT treated with vehicle, i.a. UBX, i.a. UBX plus i.p. Navi, and i.p. Navi). n = 3–5. (B) Quantification of Il4 mRNA expression in inguinal LNs (n = 3). (C) Percentage of CD4+IL-4+ T cells in inguinal LNs (n = 3). Representative flow plots of cells from LNs from young animals (no surgery, vehicle-treated, i.a. UBX–treated, and i.p. Navi–treated). (D) Percentage of weight placed on the operated limb versus the contralateral control limb (n = 4). (E) Gene expression of Il17a in inguinal LNs from WT versus Il4r–/– mice after treatment with senolytic drug (n = 3). (F) OARSI score of young WT and Il4r–/– joints treated with vehicle or senolytic drug. (G) Representative images of young WT or Il4r–/– joints treated with vehicle or senolytic drug. WT vehicle and i.a. UBX images are also shown in Figure 2F. Original magnification, ×20. Data indicate the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001, by 1-way ANOVA with Holm-Šidák multiple-comparisons test. Experimental groups were compared with the control group (vehicle).