Biofilm-derived oxylipin 10-HOME–mediated immune response in women with breast implants
Imran Khan, Robert E. Minto, Christine Kelley-Patteson, Kanhaiya Singh, Lava Timsina, Lily J. Suh, Ethan Rinne, Bruce W. Van Natta, Colby R. Neumann, Ganesh Mohan, Mary Lester, R. Jason VonDerHaar, Rana German, Natascia Marino, Aladdin H. Hassanein, Gayle M. Gordillo, Mark H. Kaplan, Chandan K. Sen, Marshall E. Kadin, Mithun Sinha
Imran Khan, Robert E. Minto, Christine Kelley-Patteson, Kanhaiya Singh, Lava Timsina, Lily J. Suh, Ethan Rinne, Bruce W. Van Natta, Colby R. Neumann, Ganesh Mohan, Mary Lester, R. Jason VonDerHaar, Rana German, Natascia Marino, Aladdin H. Hassanein, Gayle M. Gordillo, Mark H. Kaplan, Chandan K. Sen, Marshall E. Kadin, Mithun Sinha
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Research Article Immunology Inflammation

Biofilm-derived oxylipin 10-HOME–mediated immune response in women with breast implants

Abstract

This study investigates a mechanistic link of bacterial biofilm–mediated host-pathogen interaction leading to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. We report that periprosthetic breast tissue of participants with symptoms associated with BII had increased abundance of biofilm and biofilm-derived oxylipin 10-HOME compared with participants with implants who are without symptoms (non-BII) and participants without implants. S. epidermidis biofilm was observed to be higher in the BII group compared with the non-BII group and the normal tissue group. Oxylipin 10-HOME was found to be immunogenically capable of polarizing naive CD4+ T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of CD4+Th1 subtype was observed in the periprosthetic breast tissue and blood of people in the BII group. Mice injected with 10-HOME also had increased Th1 subtype in their blood, akin to patients with BII, and demonstrated fatigue-like symptoms. The identification of an oxylipin-mediated mechanism of immune activation induced by local bacterial biofilm provides insight into the possible pathogenesis of the implant-associated immune symptoms of BII.

Authors

Imran Khan, Robert E. Minto, Christine Kelley-Patteson, Kanhaiya Singh, Lava Timsina, Lily J. Suh, Ethan Rinne, Bruce W. Van Natta, Colby R. Neumann, Ganesh Mohan, Mary Lester, R. Jason VonDerHaar, Rana German, Natascia Marino, Aladdin H. Hassanein, Gayle M. Gordillo, Mark H. Kaplan, Chandan K. Sen, Marshall E. Kadin, Mithun Sinha

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Figure 7

CD4+ T cells in reaction with 10-HOME polarize macrophages to M1 phenotype.

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CD4+ T cells in reaction with 10-HOME polarize macrophages to M1 phenoty...
(A) Gene interaction networks from human bulk RNA-Seq. Upregulated genes in red and downregulated are in green, in log2 fold change. Table exhibited in Supplemental Figure 21A. (B) Increased expression of CD38 (M1 macrophage marker) in 10-HOME–treated mice compared with vehicle. Murine mammary fat pads stained with anti-CD38 antibody (DAB) and nucleus (hematoxylin). The cells in adipose tissues are bordered by adipose cells. Cells coexpressing DAB and hematoxylin were considered for analysis (arrows). Data presented as mean ± SEM, vehicle (n = 7) and 10-HOME (n = 7) mice. Scale bar: 100μm. Enlarged image in Supplemental Figure 22. (C) No significant difference of CD163 (M2 macrophage marker) in 10-HOME treated mice. Murine mammary fat pads stained with anti-CD38 antibody (DAB). Cells co-expressing DAB and hematoxylin were considered for analysis (arrows). Data presented as mean ± SEM, vehicle (n = 7) and 10-HOME (n = 7) mice. Scale bar: 100μm. Enlarged image in Supplemental Figure 23. (D) Quantification of B–C. Total number of CD38+ and CD163+ cells were calculated. Data presented as mean ± SEM, (n = 7). Mann Whitney test was used to determine vehicle versus 10-HOME CD38 (P = 0.0006) and CD163 (P = 0.558). (E) Schematic representation of macrophage/T cell transwell assay. PBMC-derived naive T cells treated with 10-HOME (blue), PBMC-derived M0 macrophages (green). (F) Increased polarization to M1 phenotype (CD86-human M1 marker) in the transwell coculture of PBMC-derived M0 macrophages incubated with10-HOME–treated naive CD4+ T cells. Flow cytometry analyses with anti-CD86 (FITC) and anti-CD14 (PE). Representative plots: vehicle treated and 10-HOME treated, histograms of cells with isotype control for CD86. Data presented as mean ± SD, (n = 8). Mann Whitney test was used for comparison of vehicle versus 10-HOME (P = 0.0152). (G) Unaltered M2 phenotype(CD163). Flow cytometry analyses with anti-CD163 (APC) and anti-CD14 (PE). Representative plots, vehicle treated and 10-HOME-treated, histograms with isotype control for CD163. Data presented as mean ± SD, (n = 8). Mann Whitney test was used to determine vehicle versus 10-HOME (P = 0.0749).