NFkappaB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles. Journal of biomedical materials research. Part A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Pajarinen, J., Maruyama, M., Nathan, K., Yao, Z., Goodman, S. B. 2018

Abstract

Total joint replacement is a highly effective treatment for patients with end-stage arthritis. Proinflammatory macrophages (M1) mediate wear particle-associated inflammation and bone loss. Anti-inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)-based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of (1) unmodified MSCs, (2) MSCs preconditioned by NFkappaB stimulating ligands [lipopolysaccharide (LPS) plus TNFalpha], and (3) genetically modified MSCs that secrete IL-4 as a response to NFkappaB activation (NFkappaB-IL4) was compared in a macrophage/MSC co-culture system. Sterile or LPS-contaminated ultra-high molecular weight polyethylene particles were used to induce the proinflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFalpha, IL1beta, and iNOS), while NFkappaB-IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg 1 and CD206 high). The IL4 secretion by NFkappaB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naive MSCs was negligible when compared with NFkappaB-IL4 MSC. Our findings indicated that NFkappaB-IL4 MSCs have the "on-demand" immunomodulatory ability to mitigate wear particle-associated inflammation with minimal adverse effects. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018.

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