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 2

Clearance of SnCs reduces the IL-17 immune signature.

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Clearance of SnCs reduces the IL-17 immune signature. (A) Quantification...
(A) Quantification of Cdkn2a mRNA expression in articular joints of young and aged mice that had no surgery (N.S.), mice that underwent sham surgery, and mice that underwent ACLT and treatment with vehicle (Veh), i.a. UBX0101 (UBX), i.a. UBX plus i.p. Navi, or i.p. Navi (n = 3–6). (B) Quantification of Il17f mRNA expression in articular joints of young and aged mice as in A (n = 3–6). (C) Percentage of weight placed on the operated limb versus the contralateral control limb by in mice as in A (n = 3–6). (D) Quantification of CD4+IL-17a+ cells from inguinal LNs of mice and representative flow plots (n = 3 for each group). (E) Quantification of mRNA expression for Il17a in inguinal LN tissue (n = 3 for each group). (F) Representative safranin-O images of joints and OARSI scores for mice as in A (n = 3–6). Original magnification, ×20. (G) Representative safranin-O images of joints and OARSI scores after ACLT and treatment with isotype or IL-17a NAb ( n = 3). Original magnification, ×20. (H) Percentage of weight placed on the operated limb versus the contralateral control limb for mice that had no surgery or mice after ACLT that were treated with either the isotype control or a IL-17a NAb (n = 9). (I) Quantification of Cdkn1a mRNA expression in articular joints (n = 3). 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. All groups were compared with each other. (A–F) Separate 1-way ANOVAs were performed for young and aged groups, and experimental groups were compared with the control group (vehicle-treated mice).