Polypropylene mesh implantation for hernia repair causes myeloid cell–driven persistent inflammation
Felix Heymann, … , Ulf P. Neumann, Frank Tacke
Felix Heymann, … , Ulf P. Neumann, Frank Tacke
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(2):e123862. https://doi.org/10.1172/jci.insight.123862.
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Research Article Gastroenterology Inflammation

Polypropylene mesh implantation for hernia repair causes myeloid cell–driven persistent inflammation

Abstract

Polypropylene meshes that are commonly used for inguinal hernia repair may trigger granulomatous foreign body reactions. Here, we show that asymptomatic patients display mesh-associated inflammatory granulomas long after surgery, which are dominated by monocyte-derived macrophages expressing high levels of inflammatory activation markers. In mice, mesh implantation by the onlay technique induced rapid and strong myeloid cell accumulation, without substantial attenuation for up to 90 days. Myeloid cells segregated into distinct macrophage subsets with separate spatial distribution, activation profiles, and functional properties, showing a stable inflammatory phenotype in the tissue surrounding the biomaterial and a mixed, wound-healing phenotype in the surrounding stromal tissue. Protein mass spectrometry confirmed the inflammatory nature of the foreign body reaction, as characterized by cytokines, complement activation, and matrix-modulating factors. Moreover, immunoglobulin deposition increased over time around the implant, arguing for humoral immune responses in association with the cell-driven inflammation. Intravital multiphoton microscopy revealed a high motility and continuous recruitment of myeloid cells, which is partly dependent on the chemokine receptor CCR2. CCR2-dependent macrophages are particular drivers of fibroblast proliferation. Thus, our work functionally characterizes myeloid cell–dependent inflammation following mesh implantation, thereby providing insights into the dynamics and mechanisms of foreign body reactions to implanted biomaterials.

Authors

Felix Heymann, Klaus-Thilo von Trotha, Christian Preisinger, Petra Lynen-Jansen, Anjali A. Roeth, Melanie Geiger, Lukas Jonathan Geisler, Anna Katharina Frank, Joachim Conze, Tom Luedde, Christian Trautwein, Marcel Binnebösel, Ulf P. Neumann, Frank Tacke

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Figure 7

Chemokine receptor CCR2-dependent alterations of mesh-associated granulomatous inflammation.

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Chemokine receptor CCR2-dependent alterations of mesh-associated granulo...
(A–C) Ccr.gfp and Ccr2–/–.gfp reporter mice were subjected to abdominal mesh surgery, and cellular infiltration was assessed using intravital TPLSM tracking of GFP+ monocytes at day 7 and day 21 after implantation. (A) TPLSM images of GFP+ monocytes day 7 and day 21 after surgery performed on Ccr2.gfp-competent and Ccr2–/–.gfp mice. Mesh fibers are visible as either black or highly fluorescent coherent structures. Blue fibers show collagen fibers visualized by second harmonic generation. Scale bar: 200 μm. For statistical analysis, cells were counted in 4 adjacent view fields surrounding mesh fibers with a penetration depth of 200 μm. (B) Migration tracking of GFP+ monocytes by intravital TPLSM. Cells were imaged and tracked over time for a period of approximately 2 hours. Migration is shown as color-coded tracks. Pink: fast moving cells ≥ 0.1 μm/sec, turquoise: slow moving cells ≤ 0.01 μm/s. Scale bar: 250 μm. (C) Statistical analysis of cellular migration shown in B, showing overall track length, cellular displacement, maximum track speed, and average track speed at day 7 and day 21. (D–G) Flow cytometry assessment of mesh-infiltrating cells. Total leukocytes and the GFP+ fraction (D) are shown. Statistical data show absolute cell counts of total leukocytes (CD45+) and monocyte-derived macrophages (GFP+Ly6G–CD11b+F4/80+). (E) GFP+ wells were subdivided into classical myeloid cell populations showing macrophage-like cells as CD11b+F4/80+ cells and activated DC-like cells as CD11c+CD86+ cells. (F and G) t-SNE analysis of myeloid cell populations infiltrating murine abdominal meshes isolated from CCR2.gfp and Ccr2–/–.gfp reporter mice at day 7 (F) and day 21 (G) after mesh implantation. Cells were pregated on CD45+GFP+ cells, and 2 × 104 cells of each genotype were concatenated and subjected to t-SNE analysis. CCR2-competent cells are highlighted in red/orange, knockout cells are highlighted in blue. Detailed expression marker profile of cells shown in the color-coded histograms. MAM, mesh-associated macrophage; SIM: stroma-infiltrating macrophage. Error bars represent mean ± SD. Student’s t test: *P < 0.05; **P < 0.01; ***P < 0.001.