NLRC3 negatively regulates Pasteurella multocida-induced NF-κB signaling in rabbits

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.