Inflammatory response is a double-edged sword. Protective inflammation can help the body clear away pathogens and tumors. However, continuous uncontrolled inflammatory response can lead to sepsis and many chronic diseases. Therefore, the inflammatory response needs to be precisely regulated to prevent its overreaction. A variety of inflammatory regulatory pathways have evolved in the body, among which the regulatory role of innervation has attracted more and more attention in recent years. Dopamine (DA) is a catecholamine neurotransmitter, and its deficiency can cause Parkinson's disease. In addition, Parkinson's patients are prone to nosocomial bacteria such as Staphylococcus aureus infection, and severe Parkinson's patients will have sepsis symptoms. Dopamine has been found to play an important role in the regulation of immune inflammation. Some studies have shown that Da inhibits NLRP3 inflammatory corpuscle and downstream inflammatory response through DRD1 signal. However, it has also been reported that Da produced by electrical stimulation of vagus nerve can extensively inhibit the expression of various inflammatory factors including TNF-a, MCP-1, IL-6 and IFN-g through D1 receptor, so as to control the occurrence of sepsis. Therefore, da-drd signal not only can regulate inflammation by inhibiting inflammatory body, but also may have other unknown complex regulatory mechanisms.
Recently, molecular cell magazine published the research results of Professor Yang Shuo's research group from Nanjing Medical University: dopamine uses the drd5-arrb2-pp2a signaling axis to block the traf6-mediated NF KB pathway and suppress systemic inflammation. This study found that after DRD5 receptor of macrophage was activated, the negative regulator arrb2 / PP2A was recruited into traf6-ikk complex through its third intracellular iyx (x) I / L structural motif and intracellular carboxyl end-tail EFD structural motif, thus blocking NF KB inflammatory signal and inhibiting Staphylococcus aureus induced sepsis and meningitis.
In this study, the researchers found that DA can specifically inhibit the NF KB inflammatory signal of macrophages mediated by Staphylococcus aureus and TLR2 pathway by sequencing histochemical analysis and inflammatory signal detection. By searching the open database and screening for dopamine receptor drugs and gene knockdown in macrophages, the researchers found that Da mainly inhibited NF KB inflammatory response of macrophages mediated by TLR2 pathway through DRD5 receptor. By analyzing all known TLR pathways, we found that Da mainly inhibited the inflammatory response mediated by TRAF6, and did not depend on cAMP-PKA signal downstream of DRD. Then, through protein biochemical experiments, the researchers proved that DRD5 recruits TRAF6 protein and its negative regulator arrb2 through the carboxy end tail EFD structural motif and the third intracellular ring iyx (x) I / L structural motif, respectively, to form drd5-arrb2-traf6 signal protein complex, and then through the arrb2 / PP2A negative regulator TRAF6 mediated NF KB inflammatory response. Finally, the researchers found that targeted activation of da-drd5 signaling significantly alleviated sepsis and meningitis caused by Staphylococcus aureus infection.
To sum up, this study revealed a new neuroimmunomodulatory signal transduction pathway, elucidated the molecular mechanism of macrophage da-drd5 signal inhibiting Staphylococcus aureus infection causing sepsis and meningitis for the first time, and provided a theoretical basis for the development of related anti-inflammatory drugs.
Professor Yang Shuo of Nanjing Medical University is the main corresponding author of this paper, and Wu Yuqing and Hu Yingchao from the Department of immunology of basic medical college are the co first authors. In the process of implementation, the project was supported by "national high level youth talent plan", "Jiangsu distinguished professor plan" and NSFC.
Original website: https://www.cell.com/molecular-cell/fulltext/s1097-2765 (20) 30043-5
Contributed by Professor Yang Shuo
Reviewed by / Galway
Editor / Zhang Yiyue
New media center, School of basic medicine, Nanjing Medical University