Abstract
Adipocytes are the most important cell type in adipose tissue playing key roles in immunometabolism. We previously reported that nine members of the Toll-like receptor (TLR) family are expressed in an originally established porcine intramuscular pre-adipocyte (PPI) cell line. However, the ability of TLR ligands to modulate immunometabolic transcriptome modifications in porcine adipocytes has not been elucidated. Herein, we characterized the global transcriptome modifications in porcine intramuscular mature adipocytes (pMA), differentiated from PPI, following stimulation with Pam3csk4, Poly(I:C) or LPS which are ligands for TLR2, TLR3, and TLR4, respectively. Analysis of microarray data identified 530 (218 up, 312 down), 520 (245 up, 275 down), and 525 (239 up, 286 down) differentially expressed genes (DEGs) in pMA following the stimulation with Pam3csk4, Poly(I:C), and LPS, respectively. Gene ontology classification revealed that DEGs are involved in several biological processes including those belonging to immune response and lipid metabolism pathways. Functionally annotated genes were organized into two groups for downstream analysis: immune response related genes (cytokines, chemokines, complement factors, adhesion molecules, and signal transduction), and genes involved with metabolic and endocrine functions (hormones and receptors, growth factors, and lipid biosynthesis). Differential expression analysis revealed that EGR1, NOTCH1, NOS2, TNFAIP3, TRAF3IP1, INSR, CXCR4, PPARA, MAPK10, and C3 are the top 10 commonly altered genes of TLRs induced transcriptional modification of pMA. However, the protein-protein interaction network of DEGs identified EPOR, C3, STAR, CCL2, and SAA2 as the major hub genes, which were also exhibited higher centrality estimates in the Gene-Transcription factor interaction network. Our results provide new insights of transcriptome modifications associated with TLRs activation in porcine adipocytes and identified key regulatory genes that could be used as biomarkers for the evaluation of treatments having immunomodularoty and/or metabolic functional beneficial effects in porcine adipocytes.
Highlights
The innate immune system recognizes infectious microbial pathogens through germ line-encoded patterns recognition receptors (PRRs), such as Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors [1]
Our results provide new insights of transcriptome modifications associated with TLRs activation in porcine adipocytes and indicate that porcine mature adipocytes (pMA) cells are an interesting tool to study in vitro the immune responses triggered by TLR2, TLR3, or TLR4 in this cell population
In our previous study we demonstrated that members of the TLR family including TLR2, TLR3, and TLR4 focused in the present study are expressed in pMA [28]
Summary
The innate immune system recognizes infectious microbial pathogens through germ line-encoded patterns recognition receptors (PRRs), such as Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors [1]. These receptors interact with the evolutionarily conserved microbial structures known as microbial associated molecular patterns (MAMPs), including lipopolysaccharides (LPS), lipoteichoic acids (LTA), peptidoglycan (PGN), and double stranded viral RNA, which are essential for the survival of microorganisms [2]. Deregulated inflammation in the adipose tissue is involved in the development metabolic disorders like obesity, atherosclerosis, and type-2 diabetes mellitus [5]. Elucidation of the cellular transcriptome modifications in adipocytes associated with the activation of their PRRs is of great importance to understand in more depth the physiopathological mechanisms involved in the metabolic diseases with an inflammatory component and to propose alternatives to prevent them
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