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Effect of Gram Negative Anaerobic Bacteria on Normal Human Skin Keratinocytes (HEKa cells)

ABSTRACT: Objectives: To define the inflammatory signature of healthy keratinocytes induced by gram-negative anaerobe bacteria commonly found in HS and investigate pathways of activation. Methods: Type strains of P. nigrescens, P. melanogenica, P. intermedia, P. asaccharolytica, F. nucleatum, as well as S. aureus and the normal skin commensal S. epidermidis were heat-killed and co-incubated with normal human keratinocytes. RNA was analyzed using RNAseq and RT-qPCR. TLR4 and JAK inhibitors were used to investigate mRNA and protein inhibition of inflammatory cytokines. Results: All GNAs tested induced significantly higher levels of CXCL8 than S. epidermidis or negative control. P. nigrescens, P. melanogenica, and F. nucleatum were the most stimulatory and produced CXCL8 levels much higher than S. aureus. RNASeq revealed a broad inflammatory profile most strongly induced by F. nucleatum. All three bacteria strongly activated the IL-17 pathway and correlated with HS skin transcriptomes. Both TLR4 and JAK inhibition significantly reduced keratinocyte inflammation. Results: All GNAs tested induced significantly higher levels of CXCL8 than S. epidermidis or negative control. P. nigrescens, P. melanogenica, and F. nucleatum were the most stimulatory and produced CXCL8 levels much higher than S. aureus. RNASeq revealed a broad inflammatory profile most strongly induced by F. nucleatum. All three bacteria strongly activated the IL-17 pathway and correlated with HS skin transcriptomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237052 | GEO | 2024/06/30

REPOSITORIES: GEO

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Project description:Bovine mastitis, an inflammatory reaction of the mammary gland, is commonly caused by Staphylococcus aureus or Escherichia coli infections in high-yielding dairy cows. Immunotranscriptomic responses of bovine mammary epithelial cell (bMEC) are pivotal for the understanding of the defense against invading pathogens, and for the fate of udder inflammation. The intracellular chemotaxic protein Cyclophilin A (CyPA), secreted by bMEC during inflammatory reaction is being considered as a marker for the early diagnosis of mastitis. Taken together, the present study aimed to investigate the microarray-based transcriptome alterations in bMEC after in vitro infection with two S. aureus strains (S. aureus JE2 and S. aureus SA003) or E. coli crude lipopolysaccharide (LPS). In addition, the CyPA-induced expression changes of selected cytokine and chemokines were evaluated by qRT-PCR. Differential expression analysis identified 447, 465 and 520 differentially expressed genes (DEGs) in bMEC after LPS, S. aureus JE2 and S. aureus SA003 stimulation, respectively. LPS-induced DEGs are involved in the activation of cytokine-cytokine receptors interaction, NOD-like receptor signaling, chemokine signaling, interleukin-1 signaling and Toll-like receptor signaling pathway; while S. aureus induced DEGs were involved in the enrichment of neuroactive ligand-receptor interaction, GPCR signaling, cytokine-cytokine receptor interaction, and JAK-STAT pathway. A major differential inflammatory response to LPS and S. aureus treatments was the activation of the chemokine signaling pathway by LPS but not either by S. aureus JE2 or SA003. Unlike the S. aureus strains, LPS stimulation resulted significant upregulation of CCL2, CXCL2, CXCL3, CXCL5, CXCL8, CXCL9, IL1A and IL1B that are known to target mononuclear leukocytes, and could induce systemic inflammation. CyPA stimulation was able to upregulate chemokines (CXCL2, CXCL3, CXCL8, IL1A and IL1B) expression in bMEC indicating its ability to promote inflammation. Several of the LPS-induced DEGs were found to have transcription factor binding sites, and their expressions were also predicted to be regulated by sets of microRNAs. The transcriptional alterations associated with inflammatory response in this study may reflect immunomodulatory mechanisms underlying the interaction of bMEC with E. coli and S. aureus during mastitis.

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Effect of Gram Negative Anaerobic Bacteria on Normal Human Skin Keratinocytes (HEKa cells)

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