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 [3,5]. It plays a pivotal role in modulating immune cell activation, mainly by inhibiting signaling pathways such as NF-κB, STING/TBK1, and inflammasome formation [3]. Additionally, it influences cell fates like proliferation, apoptosis, and pyroptosis [3].

In multiple studies, gene knockout mouse models have been crucial in understanding NLRC3's functions. NLRC3 knockout in mice promoted hypoxia-induced pulmonary hypertension development via the IKK/NF-κB p65/HIF-1α pathway, with increased right ventricular systolic pressure, hypertrophy, and fibrosis [1]. Myeloid-specific NLRC3 deletion in mice improved macrophage glycolysis and sepsis-induced immunosuppression by modulating the NF-κB-NFAT5 complex [2]. In zebrafish, Nlrc3 is required for hematopoiesis, activating the Notch pathway and its downstream gene hey1 [4]. Also, NLRC3 deficiency in mice accelerated cutaneous wound healing due to the inhibition of p53 signaling [6], and Nlrc3 knockout mice showed renal pathological changes after HTNV infection, recapitulating human HFRS symptoms [7].

In conclusion, NLRC3 is essential in immune response regulation, hematopoiesis, and wound healing. Gene knockout mouse models have been instrumental in revealing its role in diseases like hypoxia-induced pulmonary hypertension, sepsis-induced immunosuppression, and HTNV-related renal diseases. These findings provide insights into potential therapeutic targets for these conditions.

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. Cai, Shuyang, Li, Honghu, Tie, Ruxiu, Qian, Pengxu, Huang, He. 2024. Nlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates. In Nature communications, 15, 226. doi:10.1038/s41467-023-44251-6. https://pubmed.ncbi.nlm.nih.gov/38172511/

5. 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/

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/

7. 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/