Abstract
Host–pathogen interactions are complex and influenced by host genetic and epigenetic modifications. Recently, the significance of microRNAs (miRNAs) in pathogenic infection and the regulation of immune response has been highlighted. However, information on miRNAs’ role in the course of inflammation is still very limited in small ruminants. The present study was intended to identify changes in the expression of circulatory miRNAs post-lipopolysaccharide (LPS)-challenge. In this study, young ewes (n = 18) were challenged with Escherichia coli LPS (400 ng/kg i.v.) and blood samples were collected for serum miRNA isolation at two-time points; prior to challenge (T0), and 4 h (T4) post-challenge, reflecting the peak cortisol response. A total of 91 miRNAs were profiled, including 84 miRNAs on a commercial ovine miRNA-PCR array, and seven individual miRNAs. Forty five miRNAs were differentially expressed (DE) with 35 being up-regulated (Fold regulation, FR > 2) and 10 being down-regulated (FR < 1, p < 0.05) at T4. Among the up-regulated miRNAs, 14 were significantly (p < 0.05) induced, including oar-miRs: 369-3p, 495-3p, 376a-3p, 543-3p, 668-3p, 329a-3p, 655-3p, 411a-5p, and 154a-3p, which were located on ovine chromosome 18 forming four miRNA clusters within 10 kb. The elevated miRNAs belonged to different functional classes, playing roles in activating the hypothalamic-pituitary-adrenal axis; increasing cell survival and differentiation; and inducing inflammatory responses and targeted PI3K-Akt and MAPK signaling and chemokine signaling pathways. In summary, these results reveal the dynamic nature of ovine serum miRNAs during LPS-induced stress and highlight the potential role of identified miRNA-clusters on chromosome 18 to understand the regulation of the acute-phase response. Some of these identified circulating miRNAs may also serve as stress biomarkers for livestock in the future.
Highlights
Cross-talk between both neuroendocrine and immune systems occurs during microbial infection to regulate the effector response and help restore physiological homeostasis
To identify the miRNAs associated with the LPS stress challenge, the T4 post-challenge serum samples were compared with T0 pre-challenge samples
Much remains to be learned about the acute-phase response, emerging evidence highlights the importance of miRNAs in maintaining homeostasis during pathogenesis
Summary
Cross-talk between both neuroendocrine and immune systems occurs during microbial infection to regulate the effector response and help restore physiological homeostasis. PAMP making up the cell membranes of Gram-negative bacteria such as Escherichia coli, is primarily recognized by the PRR toll-like receptor 4 (TLR4). This PAMP contributes to several livestock pathologies, including mastitis [1], acidosis [2], and gut leakage due to heat stress [3]; and human pathologies, such as systematic inflammatory response syndrome and sepsis [4]. Our previous studies have utilized E. coli LPS as an acute stressor of sheep to characterize the stress response and determine the genetic contribution to variation in the stress response [5,6,7]. Several other reports have provided evidence of varying immune responses amongst sheep breeds, indicating varied genetic regulation of the innate and adaptive immune systems [8,9,10]
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