2. Academic Validation
  3. Overexpression of Toll-like receptor 4 enhances LPS-induced inflammatory response and inhibits Salmonella Typhimurium growth in ovine macrophages

Overexpression of Toll-like receptor 4 enhances LPS-induced inflammatory response and inhibits Salmonella Typhimurium growth in ovine macrophages

  • Eur J Cell Biol. 2019 Jan;98(1):36-50. doi: 10.1016/j.ejcb.2018.11.004.
Shao Wei 1,  Dongbing Yang 1,  Jifan Yang 2,  Xiaosheng Zhang 3,  Jinlong Zhang 3,  Juncai Fu 4,  Guangbin Zhou 5,  Haijun Liu 3,  Zhengxing Lian 1,  Hongbing Han 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 2 Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 3 Institute of Animal Science and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, China.
  • 4 State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China.
  • 5 Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, China.
  • 6 Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China. Electronic address: [email protected].
PMID: 30522781 DOI: 10.1016/j.ejcb.2018.11.004
Abstract

The Toll-like Receptor 4 (TLR4) plays a crucial role in innate inflammatory responses, as it recognizes gram-negative bacteria (or their products) and contributes greatly to host defense against invading pathogens. Though TLR4 overexpressing transgenic sheep, resistant to certain diseases related with gram-negative bacteria, had been bred in our previous research, the effects of overexpression of TLR4 on innate immune response remained unclear. In this study, TLR4 overexpressing ovine macrophages were obtained from peripheral blood, and it was found that the overexpression of TLR4 initially promoted the production of proinflammatory cytokines TNFα and IL-6 by activating TLR4-mediated IRAK4-dependent NF-κB and MAPK (JNK and ERK1/2) signaling following LPS stimulation. However, this effect was later impaired due to increased internalization of TLR4 into endosomal compartment of the macrophages. Then the overexpression of TLR4 triggered TBK1-dependent interferon-regulatory factor-3 (IRF-3) expression, which in turn led to the induction of IFN-β and IFN-inducible genes (i.e.IP10, IRG1 and GARG16). Understandably, an increased IFN-β level facilitated phosphorylation of STAT1 to induce expression of innate Antiviral genes Mx1 and ISG15, suggesting that TLR4 overexpressing macrophages were equipped better against viral Infection. Correspondingly, the Bacterial burden in these macrophages, after Infection with live S. Typhimurium, was decreased significantly. In summary, the results indicated that overexpression of TLR4 could enhance innate inflammatory responses, initiate the innate Antiviral immunity, and control effectively S. Typhimurium growth in ovine macrophages.

Keywords

IRAK4; Overexpression TLR4; Ovine macrophage; Salmonella; TBK1.

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