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NLRC5, the largest member of the Nod‐like receptor (NLR) family, has been reported to play a pivotal role in regulating inflammatory responses. Recent evidence suggests that NLRC5 participates in Toll‐like receptor (TLR) signaling pathways and negatively modulates nuclear factor‐κB (NF‐κB) activation. In this study, we investigated the interaction between NLRC5 and TLR2 in the NF‐κB inflammatory signaling pathway and the involvement of NLRC5 in TLR2‐mediated allergic airway inflammation. We knocked down TLR2 and NLRC5, respectively in the RAW264.7 macrophage cell line by small interfering RNA (siRNA) and then stimulated the knockdown cells with lipoteichoic acid (LTA). In comparison with the negative siRNA group, the level of NLRC5 expression was lower in the TLR2 siRNA group, with a reduction in the NF‐κB‐related inflammatory response. Conversely, in the NLRC5 knockdown cells, after LTA‐treated the level of TLR2 expression did not change but the expression levels of both NF‐κB pp65 and NLRP3 increased remarkably. Thus, we hypothesize that NLRC5 participates in the LTA‐induced inflammatory signaling pathway and regulates the inflammation via TLR2/NF‐κB. Similarly, in subsequent in vivo experiments, we demonstrated that the expression level of NLRC5 was significantly increased in the ovalbumin‐induced allergic airway inflammation. However, this effect disappeared in TLR2‐deficient (TLR2 −/−) mice and was accompanied by reduced levels of NF‐κB expression and airway inflammation. In conclusion, NLRC5 negatively regulates LTA‐induced inflammatory response via a TLR2/NF‐κB pathway in macrophages and also participates in TLR2‐mediated allergic airway inflammation. [ABSTRACT FROM AUTHOR]