NLRC3, a member of the pattern recognition receptors nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) family, is an important regulator of innate immune system homeostasis [3,4]. It plays a pivotal role in modulating immune cell activation, and is closely associated with regulatory activity rather than pathogen recognition. NLRC3 is involved in multiple signaling pathways, such as inhibiting the NF-κB, STING/TBK1, and inflammasome-related pathways [3].

NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development. In hypoxia-induced mouse models, NLRC3 knockout led to increased right ventricular systolic pressure, right ventricular hypertrophy and fibrosis. In vitro and in vivo experiments demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, HUVECs apoptosis, migration and inflammation through the IKK/NF-κB p65/HIF-1α pathway, further promoting vascular remodeling and PH progression [1]. Myeloid-specific NLRC3 deletion in mice improved macrophage glycolysis and sepsis-induced immunosuppression, as NLRC3 inhibits NF-κB p65 binding to NFAT5, controlling glycolytic genes and pro-inflammatory cytokines expression of immunosuppressive macrophages [2]. Nlrc3 knockout mice infected with HTNV developed weight loss, renal hemorrhage, and tubule dilation, showing higher viral loads and more hematological and pathological changes than wild-type mice, suggesting a new model for HFRS study [5]. In Nlrc3 gene knockout mice, skin wound repair was significantly accelerated, as NLRC3 deficiency promoted the inflammatory and proliferative phases in wounds, mainly due to regulatory effects on p53 signaling [6].

In conclusion, NLRC3 is crucial in immune response regulation, especially in innate immunity. Studies using NLRC3 knockout mouse models have revealed its roles in various disease conditions, including hypoxia-induced pulmonary hypertension, sepsis-induced immunosuppression, HFRS, and cutaneous wound healing. These findings highlight the importance of NLRC3 in disease-related biological processes and suggest potential therapeutic targets by modulating NLRC3 expression.

References:

1. Maimaitiaili, Nuerbiyemu, Zeng, Yanxi, Ju, Peinan, Zhuoga, Deji, Yu, Qing. 2023. NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway. In Experimental cell research, 431, 113755. doi:10.1016/j.yexcr.2023.113755. https://pubmed.ncbi.nlm.nih.gov/37586455/

2. Xu, Jiqian, Gao, Chenggang, He, Yajun, Yao, Shanglong, Shang, You. 2022. NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 154-173. doi:10.1016/j.ymthe.2022.08.023. https://pubmed.ncbi.nlm.nih.gov/36068919/

3. Sun, Deyi, Xu, Jiqian, Zhang, Wanying, He, Yajun, Shang, You. 2022. Negative regulator NLRC3: Its potential role and regulatory mechanism in immune response and immune-related diseases. In Frontiers in immunology, 13, 1012459. doi:10.3389/fimmu.2022.1012459. https://pubmed.ncbi.nlm.nih.gov/36341336/

4. Zhao, Yue, Li, Ruiting. 2022. Overview of the anti-inflammatory function of the innate immune sensor NLRC3. In Molecular immunology, 153, 36-41. doi:10.1016/j.molimm.2022.11.014. https://pubmed.ncbi.nlm.nih.gov/36403432/

5. Ma, Ruixue, Zhang, Xiaoxiao, Shu, Jiayi, Liu, Rongrong, Wu, Xingan. 2021. Nlrc3 Knockout Mice Showed Renal Pathological Changes After HTNV Infection. In Frontiers in immunology, 12, 692509. doi:10.3389/fimmu.2021.692509. https://pubmed.ncbi.nlm.nih.gov/34335602/

6. Qin, Yuan, Wu, Kai, Zhang, Zheng, Lu, Liting, Lu, Xincheng. 2022. NLRC3 deficiency promotes cutaneous wound healing due to the inhibition of p53 signaling. In Biochimica et biophysica acta. Molecular basis of disease, 1868, 166518. doi:10.1016/j.bbadis.2022.166518. https://pubmed.ncbi.nlm.nih.gov/35963285/