Insulin Antagonizes LPS-Induced Inflammatory Responses by Activating SR-A1/ERK Axis in Macrophages
Insulin is a key regulator of metabolism and inflammation in the body. However, the mechanism of the anti-inflammatory effect of insulin is not fully understood. In the present study, we investigated the role of the class A1 scavenger receptor (SR-A1), a prototypic member of the pattern recognition receptor family, in the insulin-mediated suppression of inflammatory responses in macrophages. Our murine in vivo studies show that insulin can attenuate lipopolysaccharide (LPS)-induced endotoxemia in a SR-A1-dependent manner, and this was consistent with our in vitro results which demonstrate that the SR-A1 is necessary for insulin to antagonize the LPS-induced inflammatory responses in macrophages. The effect of SR-A1 on the anti-inflammatory action of insulin might be associated with the activation of the extracellular signal-regulated kinases (ERK) signaling pathway in macrophages. Insulin could inhibit macrophage polarization to a pro-inflammatory phenotype via the SR-A1/ERK cascade. Collectively, our results suggest that SR-A1 may be a pivotal element for the anti-inflammation effect of insulin in macrophages.
Key Wordsinsulin lipopolysaccharide anti-inflammation scavenger receptor ERK pathway
This study was funded by grants from the National Natural Science Foundation of China (81830011, 81670418, and 91739304 to Qi Chen, 81870371 to Jingjing Ben, 81770417 to Xudong Zhu, 81670263 to Xiaoyu Li) and the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (18KJA310003 to Jingjing Ben, 15KJA310001 to Xiaoyu Li).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Nanjing Medical University (Permit Number: NJMU/IACUC-1601121).
Informed consent was obtained from all individual participants included in the study.
- 6.Yu, X., H. Yi, C. Guo, D. Zuo, Y. Wang, H.L. Kim, J.R. Subjeck, and X.Y. Wang. 2011. Pattern recognition scavenger receptor CD204 attenuates Toll-like receptor 4-induced NF-kappaB activation by directly inhibiting ubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6. The Journal of Biological Chemistry. 286: 18795–18806. https://doi.org/10.1074/jbc.M111.224345.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Kobayashi, H., N. Sakashita, T. Okuma, Y. Terasaki, K. Tsujita, H. Suzuki, T. Kodama, H. Nomori, M. Kawasuji, and M. Takeya. 2007. Class A scavenger receptor (CD204) attenuates hyperoxia-induced lung injury by reducing oxidative stress. The Journal of Pathology. 212: 38–46. https://doi.org/10.1002/path.2150.CrossRefPubMedGoogle Scholar
- 8.Zhu, X., G. Zong, L. Zhu, Y. Jiang, K. Ma, H. Zhang, Y. Zhang, H. Bai, Q. Yang, J. Ben, X. Li, Y. Xu, and Q. Chen. 2014. Deletion of class A scavenger receptor deteriorates obesity-induced insulin resistance in adipose tissue. Diabetes 63: 562–577. https://doi.org/10.2337/db13-0815.CrossRefPubMedGoogle Scholar
- 9.Zhu, X.D., Y. Zhuang, J.J. Ben, L.L. Qian, H.P. Huang, H. Bai, J.H. Sha, Z.G. He, and Q. Chen. 2011. Caveolae-dependent endocytosis is required for class A macrophage scavenger receptor-mediated apoptosis in macrophages. The Journal of Biological Chemistry. 286: 8231–8239. https://doi.org/10.1074/jbc.M110.145888.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Lu, H., D. Huang, K. Yao, C. Li, S. Chang, Y. Dai, A. Sun, Y. Zou, J. Qian, and J. Ge. 2015. Insulin enhances dendritic cell maturation and scavenger receptor-mediated uptake of oxidised low-density lipoprotein. Journal of Diabetes and its Complications 29: 465–471. https://doi.org/10.1016/j.jdiacomp.2015.03.005.CrossRefPubMedGoogle Scholar
- 17.Oshikawa, J., K. Otsu, Y. Toya, T. Tsunematsu, R. Hankins, J. Kawabe, S. Minamisawa, S. Umemura, Y. Hagiwara, and Y. Ishikawa. 2004. Insulin resistance in skeletal muscles of caveolin-3-null mice. Proceedings of the National Academy of Sciences of the United States of America 101: 12670–12675. https://doi.org/10.1073/pnas.0402053101.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Liang, C.P., S. Han, H. Okamoto, R. Carnemolla, I. Tabas, D. Accili, and A.R. Tall. 2004. Increased CD36 protein as a response to defective insulin signaling in macrophages. The Journal of Clinical Investigation. 113: 764–773. https://doi.org/10.1172/JCI19528.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Han, S., C.P. Liang, T. DeVries-Seimon, M. Ranalletta, C.L. Welch, K. Collins-Fletcher, D. Accili, I. Tabas, and A.R. Tall. 2006. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metabolism. 3: 257–266. https://doi.org/10.1016/j.cmet.2006.02.008.CrossRefPubMedGoogle Scholar