Abstract
Bovine endometritis affects milk production and reproductive performance in dairy cows and causes serious economic loss. The underlying molecular mechanisms or signaling pathways of bovine endometritis remain unclear. In this study, we attempted to determine the expression mechanism of mir-223 in endometritis of dairy cows and evaluate its potential therapeutic value. We first confirmed that there was an increased level of miR-223 in endometritis, and then, an LPS-induced bovine endometrial epithelial cell (BEND) line was used to mimic the inflammatory model in vitro. Our data showed that activation of NF-κB promoted the transcription of miR-223, thus inhibiting activation of the inflammatory mediator NLRP3 and its mediation of IL-1β production to protect against inflammatory damage. Meanwhile, in vivo studies showed that inhibition of mir-223 resulted in an enhanced pathology of mice during LPS-induced endometritis, while overexpression of mir-223 attenuated the inflammatory conditions in the uterus. In summary, our study highlights that miR-223 serves both to constrain the level of NLRP3 activation and to act as a protective factor in the inflammatory response and thus provides a future novel therapeutic modality for active flares in cow endometritis and other inflammatory diseases.
Highlights
Uterine disorders, such as endometritis, are commonly observed in high-producing dairy cows and often cause poor reproductive performance, reduced milk yield, and result in economic loss [1,2,3]
NOD-like receptor NLRP3 inflammasome is a cytoplasmic protein complex that consists of NLRP3, ASC and caspase-1, which has been shown to be a crucial regulator of diverse inflammatory diseases, including type 2 diabetes, atherosclerosis, and inflammatory bowel diseases [9, 10]
LPS is the main component of Gram-negative bacterial cell walls, and LPS-induced endometritis or uterine injury exhibits severe endometrial damage and is used to mimic these uterine disorders to evaluate the potential protection of a drug in vivo [6]. miR-223 is known to be a myeloid-enriched anti-inflammatory microRNA that migrates to sites of inflammation through myeloid cells, such as neutrophils and monocytes, causing local miR-223 levels to be significantly upregulated to exert anti-inflammatory effects
Summary
Uterine disorders, such as endometritis, are commonly observed in high-producing dairy cows and often cause poor reproductive performance, reduced milk yield, and result in economic loss [1,2,3]. The endometrium is a natural barrier, and endometrial epithelial cells can resist the invasion of foreign pathogens by regulating the immune inflammatory response [4]. Escherichia coli (E. coli), a Gram-negative bacterium, is one of the major pathogens that cause bovine endometritis via the production of the endotoxin lipopolysaccharide (LPS) [5, 6]. As the main component of Gram-negative bacteria cell walls, LPS has strong biological activity that causes a strong systemic inflammatory response through the blood circulation [7, 8]. NOD-like receptor NLRP3 inflammasome is a cytoplasmic protein complex that consists of NLRP3, ASC (apoptosis-associated speck-like protein, which contains a caspase recruitment domain) and caspase-1, which has been shown to be a crucial regulator of diverse inflammatory diseases, including type 2 diabetes, atherosclerosis, and inflammatory bowel diseases [9, 10].
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