TREM1 Enhances Macrophage Proinflammatory Response to LPS by Promoting NF-κB Activation via an IL-26–mediated JAK/STAT Signaling Pathway
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Abstract
Lipopolysaccharide (LPS)–induced inflammation in macrophages involves complex signaling pathways. This investigation explored the regulatory roles of triggering receptor expressed on myeloid cells-1 (TREM1) and interleukin (IL)-26 in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear factor-kappa B (NF-κB) p65 pathways in LPS-stimulated RAW 264.7 macrophages.
RAW 264.7 cells were treated with LPS to assess TREM1 expression. TREM1 or IL-26 was silenced using short hairpin RNA (shRNA), while IL-26 was overexpressed via plasmid transfection. The JAK2 inhibitor AG490 was used to block JAK/STAT signaling. Western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) were employed to analyze the protein and mRNA levels of inflammatory markers and signaling molecules.
Results showed that LPS upregulated TREM1 expression. In addition, TREM1 knockdown suppressed p65 activation and reduced inflammatory cytokine levels. Moreover, silencing TREM1 inhibited IL-26 and JAK/STAT phosphorylation (p-JAK1, p-JAK2, p-STAT1, and p-STAT3). Similarly, IL-26 knockdown or AG490 treatment attenuated p65 activation and inflammation. Furthermore, IL-26 overexpression reversed the anti-inflammatory effects of TREM1 silencing.
Overall, TREM1 promoted LPS-induced macrophage inflammation via IL-26–mediated JAK/STAT and NF-κB pathway activation, suggesting that TREM1 and IL-26 are potential therapeutic targets.
2. Castejon ML, Montoya T, Ortega-Vidal J, et al. Ligstroside aglycon, an extra virgin olive oil secoiridoid, prevents inflammation by regulation of mapks, jak/stat, nf-kappab, nrf2/ho-1, and nlrp3 inflammasome signaling pathways in lps-stimulated murine peritoneal macrophages. Food Funct. 2022;13:10200-9.
3. Tran N, Mills EL. Redox regulation of macrophages. Redox Biol. 2024;72:103-23.
4. Zhang H, Ge S, Ni B, et al. Augmenting atg14 alleviates atherosclerosis and inhibits inflammation via promotion of autophagosome-lysosome fusion in macrophages. Autophagy. 2021;17:4218-30.
5. Tang PM, Nikolic-Paterson DJ, Lan H. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol. 2019;15:144-58.
6. Peng Y, Zhou M, Yang H, et al. Regulatory mechanism of m1/m2 macrophage polarization in the development of autoimmune diseases. Mediators Inflamm. 2023;2023:8821610.
7. Li C, Cai C, Xu D, et al. Trem1: activation, signaling, cancer and therapy. Pharmacol Res. 2024;204:107212.
8. Siskind S, Brenner M, Wang P. Trem-1 modulation strategies for sepsis. Front Immunol. 2022;13:907387.
9. Huynh K. Atherosclerosis: trem1 in atherosclerosis development. Nat Rev Cardiol. 2017;14:67.
10. Ren L, Qiao G, Zhang S, et al. Pharmacological inhibition or silencing of trem1 restrains hcc cell metastasis by inactivating tlr/pi3k/akt signaling. Cell Biochem Biophys. 2024;82:2673-85.
11. Sun S, Fan Z, Liu X, et al. Microglia trem1-mediated neuroinflammation contributes to central sensitization via the nf-kappab pathway in a chronic migraine model. J Headache Pain. 2024;25:3.
12. Fan D, He X, Bian Y, et al. Triptolide modulates trem-1 signal pathway to inhibit the inflammatory response in rheumatoid arthritis. Int J Mol Sci. 2016;17:498.
13. Xin P, Xu X, Deng C, et al. The role of jak/stat signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020;80:106210.
14. Huang I, Chung W, Wu P, et al. Jak-stat signaling pathway in the pathogenesis of atopic dermatitis: an updated review. Front Immunol. 2022;13:1068260.
15. Herrera-Deguise C, Serra-Ruiz X, Lastiri E, et al. Jak inhibitors: a new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne). 2023;10:1089099.
16. Lawrence T. The nuclear factor nf-kappab pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1:a1651.
17. Mulero MC, Huxford T, Ghosh G. Nf-kappab, ikappab, and ikk: integral components of immune system signaling. Adv Exp Med Biol. 2019;1172:207-26.
18. Zhang N, Han L, Xue Y, et al. The protective effect of magnesium lithospermate b on hepatic ischemia/reperfusion via inhibiting the jak2/stat3 signaling pathway. Front Pharmacol. 2019;10:620.
19. Alyamac A, Ozel-Tasci C, Gulec S. The effect of ankaferd blood stopper on colonic inflammation: an in vitro study in raw 264.7 and caco-2 cells. J Med Food. 2021;24:1280-4.
20. Widowati W, Kusuma HSW, Arumwardana S, et al. Corilagin potential in inhibiting oxidative and inflammatory stress in lps-induced murine macrophage cell lines (raw 264.7). Iran J Basic Med Sci. 2021;24:1656-65.
21. de Campos GY, Oliveira RA, Oliveira-Brito PKM, et al. Pro-inflammatory response ensured by lps and pam3csk4 in raw 264.7 cells did not improve a fungistatic effect on cryptococcus gattii infection. PeerJ. 2020;8:e10295.
22. Zhong W, Liu T, Yang H, et al. Trem-1 governs nlrp3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury. Int J Biol Sci. 2023;19:242-57.
23. Dong M, Zhang X, Peng P, et al. Hypoxia-induced trem1 promotes mesenchymal-like states of glioma stem cells via alternatively activating tumor-associated macrophages. Cancer Lett. 2024;590:216801.
24. Read CB, Kuijper JL, Hjorth SA, et al. Cutting edge: identification of neutrophil pglyrp1 as a ligand for trem-1. J Immunol. 2015;194:1417-21.
25. Li Z, Wu F, Xu D, et al. Inhibition of trem1 reduces inflammation and oxidative stress after spinal cord injury (sci) associated with ho-1 expressions. Biomed Pharmacother. 2019;109:2014-21.
26. Tengvall S, Che KF, Linden A. Interleukin-26: an emerging player in host defense and inflammation. J Innate Immun. 2016;8:15-22.
27. Truong AD, Hong Y, Hoang CT, et al. Chicken il-26 regulates immune responses through the jak/stat and nf-kappab signaling pathways. Dev Comp Immunol. 2017;73:10-20.
28. Rudick CP, Cornell DL, Agrawal DK. Single versus combined immunoregulatory approach using pd-1 and ctla-4 modulators in controlling sepsis. Expert Rev Clin Immunol. 2017;13:907-19.
29. Xiong B, Li C, Hong G, et al. Hmgb1/trem1 crosstalk between heat-injured hepatocytes and macrophages promotes hcc progression after rfa. J Cancer Res Clin Oncol. 2024;150:480.
30. O'Shea JJ, Plenge R. Jak and stat signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36:542-50.
31. He W, Qian QW, Liu QY, et al. Il-26 modulates t cell function in autoimmune hepatitis. J Dig Dis. 2023;24:231-42.
32. Campbell GR, To RK, Spector SA. Trem-1 protects hiv-1-infected macrophages from apoptosis through maintenance of mitochondrial function. mBio. 2019;10.
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| Keywords | ||
| IL-26 Inflammation JAK/STAT Macrophages NF-κB TREM1 | ||
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