Deciphering Key Foreign Body Reaction-Related Transcription Factors and Genes Through Transcriptome Analysis

Abstract

Background: Silicone implants are widely used in the field of plastic surgery for wound repair and cosmetic augmentation. However, molecular mechanisms and signaling pathways underlying the foreign body reaction (FBR) of a host tissue to the silicone require further elucidation. The purpose of this study was to identify key FBR-related transcription factors (TFs) and genes through transcriptome analysis.Methods: We used a rat model with a subcutaneous silicone implant in the scalp and performed high throughput sequencing to determine the transcriptional profiles involved in the FBR. The function was analyzed by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-enrichment analysis. A protein-protein interaction (PPI) network of differentially expressed mRNAs (DEmRNAs) was constructed to identify the hub genes and key modules and to determine the regulatory TF-mRNA relationships. In addition, the hub gene and transcript expression levels were determined by Quantitative Reverse Transcription polymerase Chain Reaction (qRT-PCR). Myofibroblasts differentiation and macrophage recruitment were identified by immunofluorescence. The protein expression of MMP9 was detected by immunohistochemistry and Western blot.Results: We identified ten hub genes (Fos, Spp1, Fn1, Ctgf, Tlr2, Itgb2, Itgax, Ccl2, Mmp9, and Serpine1) and 3 TFs (FOS, IRF4, and SPI1) that may be crucial (particularly FOS) for the FBR. Furthermore, we identified multiple differentially expressed genes involved in several important biological processes, including leukocyte migration, cytokine‒ cytokine receptor interaction, phagocytosis, extracellular matrix (ECM) organization, and angiogenesis. We also identified potentially significant signaling pathways, including cytokine‒cytokine receptor interaction, phagosome, ECM‒receptor interaction, complement and coagulation cascades, the IL-17 signaling pathway, and the PI3K‒Akt signaling pathway. In addition, qRT-PCR confirmed the expression patterns of the TFs and hub genes, Western blot and immunohistochemistry validated the expression patterns of MMP9.Conclusion: We generated a comprehensive overview of the gene networks underlying the FBR evoked by silicone implants. Moreover, we identified specific molecular and signaling pathways that may perform key functions in the silicone implant-induced FBR. Our results provide significant insights into the molecular mechanisms underlying silicone-induced FBR and determine novel therapeutic targets to reduce complications related to silicone implantation.

The extended effect of adsorbed damage-associated molecular patterns and Toll-like receptor 2 signaling on macrophage-material interactions

“…These general trends were reproduced in the present study for RAW-Blue macrophages cultured on the 10% FBS-conditioned surfaces. Furthermore, the absence of an effect due to TLR2 inhibition supports established views that macrophage activation in traditional culture environments that use serum-derived adsorbed protein layers does not involve TLR2 and may explain why this signaling pathway has been largely overlooked in sterile biomaterial-induced inflammation and FBR until recently (Li et al, 2019;Liu et al, 2022). Frontiers in Bioengineering and Biotechnology frontiersin.org…”

“…MyD88-deficient mice had reduced inflammatory cell recruitment and thinner fibrous capsules when compared to wild type mice, 28 days after PEG hydrogel implantation (Amer et al, 2019). In a recent study by Liu and colleagues identified the TLR2-encoding gene Tlr2 as a critical gene hub in the FBR to silicone implants in rats (Liu et al, 2022).…”

Engineered collagen polymeric materials create noninflammatory regenerative microenvironments that avoid classical foreign body responses

“…4G). 58 Informed by KEGG analysis outcomes, more detailed evaluations of gene subsets were conducted, beginning with those related to innate immune cell (e.g., neutrophil and macrophage) phenotype and activation. As shown in Fig.…”

Mechanical Stretch Induced Skin Regeneration: Molecular and Cellular Mechanism in Skin Soft Tissue Expansion

“…Several transcription factors (Fos, FosL1, LEF1, TCF7, HMGA1, ELF5, IRF4, SPI1) have also been identified that may be crucial in skin soft tissue expansion [ 48 , 107 ]. FOS and FOSL1 are members of the Fos gene family and the proteins encoded by them can dimerize with Jun family proteins to form the transcription factor complex AP-1.…”

“…We discussed previously that mechanical stretch can induce the activation of Wnt/β-catenin signaling pathway to promote skin soft tissue expansion. ELF5, IRF4, and SPI1 are important transcription factors that regulate the differentiation, activation, and proliferation of immune cells and are believed to be involved in the foreign body response to silicone during tissue expansion [ 107 ].…”