An efficient host defense mechanism is necessary for human beings to survive in an environment full of microbes. The first line of defense and the most rapid response against microbial invasion are provided by the innate immune system. The innate immune system directly recognizes microorganisms through pattern recognition receptors (PRRs), which detect microbial molecules or components foreign to the host. Pathogen-associated molecular patterns (PAMPs) comprise microbial molecular components that can be recognized by PRRs. These receptors can also recognize damage-related molecular patterns (DAMPs) released after tissue injury due to inflammation or other causes. This initiates a series of inflammatory responses that play a defensive role. Although microbes invade the body daily, we rarely exhibit symptoms of infection-related inflammation. Even when the symptoms occur, they rapidly fade away after the microbes are suppressed by the immune system. This highlights the potential of the innate immune system in not only promoting the inflammatory response but also regulating and limiting the inflammatory process to achieve immune homeostasis.

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) regulates innate immune system homeostasis. It is the intracellular PRR of PAMP and DAMP, and a key component of the inflammasome complex. The inflammasome complex is a polyprotein complex that activates Caspase-1, resulting in the subsequent production of active key pro-inflammatory cytokines, such as interleukin (IL)− 1β and IL-18. This leads to a strong immune response, thus eliminating pathogens. Additionally, the members of the anti-inflammatory NLR family maintain a balance between immune activation and immune weakening by inhibiting the strong immune response and suppressing inflammation after eliminating the pathogen (Chen et al., 2009).

NLR family CARD domain-containing protein 3 (NLRC3) is a member of the NLR innate immune receptor family. It is an anti-inflammatory NLR found during screening for proteins and nucleotide binding domains rich in leucine repeats (Conti et al., 2005, Harton et al., 2002). NLRC3 negatively regulates CD4+ T cells and affects protective immunity in response to viruses, bacteria (Mycobacterium tuberculosis), and autoantigens (Uchimura et al., 2018, Hu et al., 2018, Gultekin et al., 2015). NLRC3 also plays an anti-cancerous role in colon cancer by inhibiting colitis-related tumorigenesis (Karki et al., 2016, Karki et al., 2017). It interferes with the progression of human hepatocellular carcinoma through the IL-6/Janus kinase2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) pathways (Kang et al., 2020). Therefore, understanding the mechanism of action of NLRC3 might contribute to the treatment of infectious diseases, autoimmune diseases, and cancer. In this study, we reviewed the mechanism by which NLRC3 inhibits inflammatory responses and its role in the inflammatory signaling pathway.