Negative regulator NLRC3: Its potential role and regulatory mechanism in immune response and immune-related diseases

Abstract

NLRC3 is a member of the pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family, and plays a pivotal regulatory role in modulating the activation of immune cells. In macrophages, NLRC3 inhibits the activation of the NF-κB signaling pathway, the STING/TBK1 signaling pathway, and the formation of the inflammasome. In the context of T cells immune response, NLRC3 prevents the activation of T cells by regulating the function of dendritic cells and directly influencing the function of T cells. Different from other pattern recognition receptors, NLRC3 is more closely associated with regulatory activity than pathogens recognition, it influences the fates of cells, for example, prevents proliferation, promotes apoptosis and inhibits pyroptosis. These cellular functions regulated by NLRC3 are involved in the development processes of a variety of diseases, such as infectious disease, sterile inflammatory diseases, and cancer. However, its characteristics, function and regulatory mechanism in immune response and immune-related diseases have not been addressed fully. In this review, we elaborate the potential roles of NLRC3 from several different levels, include molecular mechanism, cellular functions in the immune-related diseases.

Rotating Magnetic Field Mitigates Ankylosing Spondylitis Targeting Osteocytes and Chondrocytes via Ameliorating Immune Dysfunctions

“…NLRC3 is an intracellular member of the NLR family and was originally discovered in T-cells. NLRC3 is expressed at a reduced level in bone marrow cells and acts as an inhibitor of inflammatory signaling [ 81 ]. The absence of NLRC3 stimulates the differentiation of CD4 + T-cells into Th1 and Th17 subsets, leading to the development of various diseases [ 82 ].…”

“…The absence of NLRC3 stimulates the differentiation of CD4 + T-cells into Th1 and Th17 subsets, leading to the development of various diseases [ 82 ]. NLRC3 is abundantly expressed in T-cells, and a growing amount of evidence indicates that it performs as a suppressor of T-cell response [ 81 , 82 ]. NLRC3 depletion in AS mice might account for the substantial inflammatory response and elevated IL-17A production.…”

Transcriptomic responses of Mediterranean sponges upon encounter with seawater or symbiont microbial consortia

“…We speculate that the different types of NLRs (i.e., NLRC3, NLRC4 and NLRP3) activate different downstream signaling pathways in D. avara whose ultimate goal is to regulate microbial recognition by the sponge. In humans and mice these NLR families regulate inflammatory pathways (Pan et al, 2022; Schneider et al, 2013; Sun et al, 2022; Uchimura et al, 2018; Walle & Lamkanfi, 2016). Inflammation requires various post-translational modifications comprising ubiquitin ligases, kinases and phosphatases (Akther et al, 2021; Song & Li, 2018; Yang et al, 2017), and the ubiquitin system, which is crucial in many biological process, is proposed as an essential innate immunity regulator and as a modulator of host-microbe interactions (Li et al, 2016; Zhang et al, 2021).…”

“…The best hits of differentially-expressed D. avara NLRs in E. muelleri support that the NLRs activated in response to seawater bacteria belong to a different NLR subfamily than the one responding to A. aerophoba symbiont consortia (Table S7). In humans and mice these NLR families regulate inflammatory pathways (Pan et al, 2022;Schneider et al, 2013;Sun et al, 2022;Uchimura et al, 2018;Walle & Lamkanfi, 2016).…”

Signaling pathways in macrophages: molecular mechanisms and therapeutic targets

“…65 In contrast to NLRP3, NLRC3 inhibits macrophage activation and prevents inflammatory factor production by negatively regulating multiple inflammatory pathways. 60 For example, NLRC3 can inhibit the activation of TRAF6 and IRAK1 and promote their degradation, thus inhibiting the activation of NF-κB signaling. 66 In addition, NLRC3 can disrupt the formation of inflammasomes by blocking the ASC and pro-caspase-1 interaction through the CARD domain.…”