NFκB sensing IL‐4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles

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 NFκB stimulating ligands [lipopolysaccharide (LPS) plus TNFα], and (3) genetically modified MSCs that secrete IL-4 as a response to NFκB activation (NFκB-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 (TNFα, IL1β, and iNOS), while NFκB-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 NFκB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naïve MSCs was negligible when compared with NFκB-IL4 MSC. Our findings indicated that NFκB-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: 106A: 2744-2752, 2018.

Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment

“…In addition, training MSCs by exposure to inflammatory cytokines and other substances appears to impart an innate immune memory of the prior stimulus [179]. We have also developed NF-κB sensing and IL-4 over-expressing genetically modified MSCs to treat chronic inflammation [176,180]. Local delivery of these modified MSCs may have a future role in the treatment of PPOL.…”

Effect of Aging on the Macrophage Response to Titanium Particles

“…Wear particles together with inflammatory microenvironmental signals induce an M1‐like macrophage polarization that exacerbates the production of pro‐inflammatory mediators and favors osteoclastogenesis . In contrast, alternatively activated M2 macrophage phenotype is proposed to mitigate these adverse effects, and an M2 supporting immunomodulatory strategy has emerged as a promising means to counteract the particle‐induced inflammation and potentially increase the lifespan of the implant . Thus, M1 and M2 macrophages are seen as the opposite ends of the continuum of macrophage phenotypes where M0 represents a non‐polarized activation state.…”

PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration

“…Leakage of IL-4 into the systemic circulation could potentially increase the risk of infection [26,27], allergic reactions [28] and synovial hyperplasia [29]. Previous research using novel NF-kB sensing IL-4 secreting MSCs which had similar expression level with the co-infection GM MSCs in this study could potentially mitigate inflammation-associated problems and reduce the adverse effects of excessive IL-4 secretion [5,18]. Constitutive promoters of lentiviral vector were widely used in GM MSCs to obtain sufficient doses of the target proteins [30]; Strong CMV promotor of in IL-4 vector [5,9] and relatively weak PGK promotor in PDGF-BB vector [8] were used in this study to generate GM MSCs based on previous studies.…”

“…In order to monitor potential adverse effects of excessive IL-4 and PDGF-BB, an in vivo study is necessary. Further investigation will also be conducted using inflammation regulated GM MSCs such as with NF-kB sensing [5,18] In vivo confirmation of these findings of using GM MSCs in animal models of inflammatory bone loss [36] and nonunion in critical-size bone defects [37] are needed to confirm these in vitro observations.…”

“…MSCs have been applied as gene carriers to enhance the therapeutic capability in tissue regeneration and treatments of various diseases [17]. GM MSCs that overexpress IL-4 modulated inflammatory macrophages into an anti-inflammatory phenotype [18] which augmented osteogenesis of MSCs in coculture with macrophages [3,19,20]. Inflammation is the first stage of bone formation and fracture healing.…”