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Abstract
Bovine mammary epithelial cells (bMECs) contribute to mammary gland defense against invading pathogens, such as Staphylococcus aureus (intracellular facultative), which is recognized by TLR2. In a previous report, we showed that sodium octanoate [NaO, a medium chain fatty acid (C8)] induces (0.25 mM) or inhibits (1 mM) S. aureus internalization into bMECs and differentially regulates the innate immune response (IIR). However, the molecular mechanisms have not been described, which was the aim of this study. The results showed that α5β1 integrin membrane abundance (MA) was increased in 0.25 mM NaO-treated cells, but TLR2 or CD36 MA was not modified. When these receptors were blocked individually, 0.25 mM NaO-increased S. aureus internalization was notably reduced. Interestingly, in this condition, the IIR of the bMECs was impaired because MAPK (p38, JNK, and ERK1/2) phosphorylation and the activation of transcription factors related to these pathways were decreased. In addition, the 1 mM NaO treatment induced TLR2 MA, but neither the integrin nor CD36 MA was modified. The reduction in S. aureus internalization induced by 1 mM NaO was increased further when TLR2 was blocked. In addition, the phosphorylation levels of the MAPKs increased, and 13 transcriptional factors related to the IIR were slightly activated (CBF, CDP, c-Myb, AP-1, Ets-1/Pea-3, FAST-1, GAS/ISRE, AP-2, NFAT-1, OCT-1, RAR/DR-5, RXR/DR-1, and Stat-3). Moreover, the 1 mM NaO treatment up-regulated gene expression of IL-8 and RANTES and secretion of IL-1β. Notably, when 1 mM NaO-treated bMECs were challenged with S. aureus, the gene expression of IL-8 and IL-10 increased, while IL-1β secretion was reduced. In conclusion, our results showed that α5β1 integrin, TLR2 and CD36 are involved in 0.25 mM NaO-increased S. aureus internalization in bMECs. In addition, 1 mM NaO activates bMECs via the TLR2 signaling pathways (p38, JNK, and ERK1/2), which improves IIR before S. aureus invasion. Additionally, NaO (1 mM) might exert anti-inflammatory effects after bacterial internalization.
Highlights
Medium chain fatty acids (8–14 carbons, MCFAs) are an important energy source present in several foods as medium chain triglycerides (Nagao and Yanagita, 2010)
We showed that α5β1 integrin, TLR2, and CD36 play an important role in 0.25 mM NaOincreased S. aureus internalization, but the innate immune response (IIR) of Bovine mammary epithelial cells (bMECs) is impaired
In the same condition, the blockage of α5β1 integrin or CD36 did not modify the effect of this MCFA (Figures 1A,C). These effects were specific because the bacterial internalization was not modified in mouse or rat IgG-treated cells. These results suggest that α5β1 integrin, TLR2, and CD36 are involved in the 0.25 mM NaO-increased S. aureus internalization into bMECs
Summary
Medium chain fatty acids (8–14 carbons, MCFAs) are an important energy source present in several foods as medium chain triglycerides (i.e., coconut and palm kernel oil, butter, milk, yogurt, and cheese) (Nagao and Yanagita, 2010). MCFAs possess in vitro antimicrobial properties against human gastrointestinal (Marounek et al, 2003; Skrivanova and Marounek, 2007; Aydin et al, 2011) and bovine mastitis pathogens (e.g., Staphylococcus aureus) (Nair et al, 2005). A few studies have described the immunomodulation capacity of octanoate in intestinal epithelial cells (non-professional phagocytic cells, NPPCs), focusing on the inflammatory response (Andoh et al, 2000; Tanaka et al, 2001; Hoshimoto et al, 2002) and the antimicrobial peptide (AP) gene expression (Sunkara et al, 2012; Jiang et al, 2013; Zeng et al, 2013). The innate immune response (IIR) is a first-line defense mechanism against invading pathogens. Epithelial cells (ECs) participate in this defense through pattern recognition of conserved molecules associated with microorganisms (PAMPs) by means of various families of germ-line-encoded patternrecognition receptors, including the Toll-like receptors (TLRs) (Bulek et al, 2010). The production of innate immune effectors (enzymes, AP, cytokines, chemokines) is due to the stimulation of ECs through diverse receptors, which in turn leads to the activation of MAPK family proteins (p38, JNK and ERK1/2) and transcription factors (e.g., NF-κB, AP-1, E2F-1, EGR, FAST-1) (Akira et al, 2006; Chiu et al, 2009; Alva-Murillo et al, 2015; Medina-Estrada et al, 2015)
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