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NLRC3 negatively regulates Pasteurella multocida-induced NF-κB signaling in rabbits
Mengjiao Guo1, Jiaqi Zhang1, Mingtao Li1
1Jiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
Abstract:
Pasteurella multocida (P. multocida) is a significant zoonotic pathogen that has the ability to infect various animals. The inflammatory response caused by P. multocida and the negative regulatory mechanism are not completely understood. NOD-like receptor family CARD-containing 3 (NLRC3), an intracellular member of the NLR family, has been reported as a negative regulator in human. In this study, we aimed to explore the role of rabbit NLRC3 (rNLRC3) in P. multocida infection. Our findings revealed a negative correlation between the expression of rNLRC3 and inflammatory cytokines during P. multocida infection. The expression of rNLRC3 was reduced at the initial stage of P. multocida infection and then recovered. Furthermore, rNLRC3 significantly inhibited the activation of NF-κB by reducing phosphorylation and nuclear import of p65 in response to P. multocida infection. Additionally, overexpression of rNLRC3 attenuated the expression of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α. Moreover, we demonstrated that rNLRC3 diminished NF-κB activation by interacting with rTRAF4 and rTRAF6. Overexpression of rNLRC3 promoted P. multocida proliferation, while P. multocida proliferation decreased after knockdown of rNLRC3. We also found that the NACHT-LRR domain is a functional domain of rNLRC3 that regulates the NF-κB pathway. Our study suggests that rNLRC3 negatively regulates P. multocida-induced NF-κB signaling in rabbits. It can serve as a checkpoint to prevent dysfunctional inflammation.
Insights
Rabbit NLRC3 (NOD-like receptor family CARD-containing 3) negatively regulates Pasteurella multocida infection by inhibiting NF-κB signaling. This finding reveals NLRC3 as a potential checkpoint to prevent excessive inflammation in rabbits.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Pasteurella multocida is a zoonotic pathogen causing significant infections in animals.
- The precise mechanisms of inflammatory response and its negative regulation during P. multocida infection are not fully understood.
- NOD-like receptor family CARD-containing 3 (NLRC3) acts as an intracellular negative regulator of inflammation in humans.
Purpose of the Study:
- To investigate the role of rabbit NLRC3 (rNLRC3) in the context of P. multocida infection.
- To elucidate the regulatory function of rNLRC3 in the inflammatory response and NF-κB signaling pathway.
Main Methods:
- Analysis of rNLRC3 expression levels in response to P. multocida infection.
- Investigation of rNLRC3's effect on NF-κB pathway activation (p65 phosphorylation and nuclear import).
- Assessment of rNLRC3's interaction with TRAF4 and TRAF6, and its impact on pro-inflammatory cytokine production (IL-1β, IL-6, IL-8, TNF-α).
- Evaluation of rNLRC3's role in P. multocida proliferation through overexpression and knockdown experiments.
- Identification of the functional domain of rNLRC3 involved in NF-κB pathway regulation.
Main Results:
- A negative correlation was observed between rNLRC3 expression and inflammatory cytokines during P. multocida infection.
- rNLRC3 expression decreased initially and then recovered during infection.
- rNLRC3 significantly inhibited NF-κB activation and attenuated pro-inflammatory cytokine expression.
- rNLRC3 interacted with rTRAF4 and rTRAF6, modulating NF-κB signaling.
- Overexpression of rNLRC3 promoted P. multocida proliferation, while knockdown decreased it.
- The NACHT-LRR domain was identified as the functional domain of rNLRC3 for NF-κB pathway regulation.
Conclusions:
- Rabbit NLRC3 acts as a negative regulator of P. multocida-induced NF-κB signaling in rabbits.
- rNLRC3 functions as a critical checkpoint to prevent excessive or dysfunctional inflammation.
- Understanding rNLRC3's role provides insights into host-pathogen interactions and potential therapeutic targets for P. multocida infections.
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