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Int J Biol Sci 2023; 19(1):242-257. doi:10.7150/ijbs.77304 This issue Cite

Research Paper

TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

Wen-Jing Zhong1, Tian Liu2, Hui-Hui Yang1, Jia-Xi Duan3, Jin-Tong Yang1, Xin-Xin Guan1, Jian-Bing Xiong1, Yan-Feng Zhang4, Chen-Yu Zhang1, Yong Zhou1✉, Cha-Xiang Guan1✉

1. Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
2. College of Physiology Education, Chongqing University of Arts and Science, Chongqing 412160, China
3. Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
4. Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

✉ Corresponding authors: Prof. Cha-Xiang Guan or Yong Zhou; Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China. Tel.: +86-731-82355051; Fax: +86-731-82355056; E-mail: guanchaxiangedu More

Citation:
Zhong WJ, Liu T, Yang HH, Duan JX, Yang JT, Guan XX, Xiong JB, Zhang YF, Zhang CY, Zhou Y, Guan CX. TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. Int J Biol Sci 2023; 19(1):242-257. doi:10.7150/ijbs.77304. https://www.ijbs.com/v19p0242.htm
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Abstract

Graphic abstract

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1α (HIF-1α) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1α accumulation and translocation to the nucleus via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Inhibiting mTOR or HIF-1α also suppressed TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. Overall, the mTOR/HIF-1α/glycolysis pathway is a novel mechanism underlying TREM-1-governed NLRP3 inflammasome activation. Therapeutic targeting of the mTOR/HIF-1α/glycolysis pathway in TREM-1-activated macrophages could be beneficial for treating or preventing inflammatory diseases, such as ALI.

Keywords: Acute lung injury, TREM-1, glycolysis, NLRP3 inflammasome, HIF-1α, macrophages

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APA
Zhong, W.J., Liu, T., Yang, H.H., Duan, J.X., Yang, J.T., Guan, X.X., Xiong, J.B., Zhang, Y.F., Zhang, C.Y., Zhou, Y., Guan, C.X. (2023). TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. International Journal of Biological Sciences, 19(1), 242-257. https://doi.org/10.7150/ijbs.77304.

ACS
Zhong, W.J.; Liu, T.; Yang, H.H.; Duan, J.X.; Yang, J.T.; Guan, X.X.; Xiong, J.B.; Zhang, Y.F.; Zhang, C.Y.; Zhou, Y.; Guan, C.X. TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. Int. J. Biol. Sci. 2023, 19 (1), 242-257. DOI: 10.7150/ijbs.77304.

NLM
Zhong WJ, Liu T, Yang HH, Duan JX, Yang JT, Guan XX, Xiong JB, Zhang YF, Zhang CY, Zhou Y, Guan CX. TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. Int J Biol Sci 2023; 19(1):242-257. doi:10.7150/ijbs.77304. https://www.ijbs.com/v19p0242.htm

CSE
Zhong WJ, Liu T, Yang HH, Duan JX, Yang JT, Guan XX, Xiong JB, Zhang YF, Zhang CY, Zhou Y, Guan CX. 2023. TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. Int J Biol Sci. 19(1):242-257.

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