CN112023050A - Method for regulating polarization state of macrophage - Google Patents
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Abstract
The present invention provides a method for modulating the polarization state of macrophages, said method comprising the step of activating the cholinergic anti-inflammatory pathway of the macrophages with a cholinergic anti-inflammatory pathway agonist and/or a vagal electrical stimulation signal. The invention adopts the cholinergic anti-inflammatory pathway stimulant to stimulate the macrophage in vitro or adopts the electrical stimulation signal to stimulate the vagus nerve in vivo, activates the cholinergic anti-inflammatory pathway, inhibits the polarization of M1 type macrophages, promotes the polarization of M2 type macrophages, realizes the regulation effect on the polarization type of the macrophages, and has important significance in the aspect of specifically regulating the functions of the polarized macrophages and diseases caused by the macrophages.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a method for regulating the polarization state of macrophages, and particularly relates to a method for regulating the polarization state of macrophages by activating a cholinergic anti-inflammatory pathway and application thereof in delaying the generation and development of atherosclerosis inflammation.
Background
Macrophages are formed by differentiation of myeloid progenitor cells into monocytes, which migrate into the blood and into tissues. Macrophages are classified into classical (M1 type) and alternate (M2 type) types according to differences in activation pattern and function. Under stimulation of bacterial toxin LPS or Th1 cytokines (TNF alpha, IFN gamma) and the like, macrophages are activated and polarized into M1 type, express and release proinflammatory factors and active oxygen, and have the effects of killing pathogens, eliminating necrotic tissues and promoting inflammatory reaction; correspondingly, under the induction of Th2 cytokines (IL-4, IL-13) and the like, macrophages are activated into M2 type, express anti-inflammatory factors (such as TGF beta and IL-10), and have the effects of relieving inflammation, promoting tissue growth and repairing. In addition, the polarization state of macrophages can also be regulated by changing the expression of genes such as Krluppel-like factors (KLF4), STAT6, miR-33 and the like.
Researches find that two different polarized macrophages have important regulation and control functions in the generation process of inflammatory diseases, and can be mutually converted in function when different microenvironments respond to different stimuli; and the function of M1 type macrophages is blocked, the anti-inflammatory repair property of M2 type polarized cells is maintained, and the anti-inflammatory agent plays an important role in inhibiting the generation and development of inflammation. Therefore, finding an effective way to modulate the polarization state of macrophages is of great importance in the prevention and treatment of inflammation-related diseases. However, there are currently fewer effective methods of modulating macrophage polarization.
The Cholinergic Anti-inflammatory Pathway (CAP) is a newly discovered neuroimmunomodulatory Anti-inflammatory Pathway. Under the condition of inflammation, an afferent vagus nerve (afferent vagus) transmits an inflammation signal to a central nervous system, and Acetylcholine (ACh) is released by an efferent vagus nerve (efferent vagus) to act on macrophages, so that the release of cell inflammatory factors is reduced, and the development of inflammatory reaction can be effectively inhibited. CAP has obvious inhibition effect on systemic and local inflammation, and provides an effective way for regulating the function of cell factors and relieving inflammation-related diseases. Research shows that the stimulation of vagus nerve to activate CAP can inhibit the occurrence and development of diseases such as acute inflammation, sepsis, chronic rheumatoid arthritis and the like, thereby improving the disease symptoms. At present, the method for stimulating the vagus nerve is approved by the FDA in the United states and is applied to the prevention and treatment of epilepsy, rheumatoid arthritis and other diseases.
Atherosclerosis is a chronic inflammatory disease, the main cause of which is abnormal lipid metabolism and accumulation on the vascular endothelium, causing inflammation, exacerbating plaque and thrombus formation, and leading to vascular blockage. The inflammatory response is consistently throughout the various stages of the development, progression and evolution of atherosclerosis, and may be the central component of the pathogenesis of multiple causative factors of atherosclerosis. At the initial stage of atherosclerosis, the inflammatory reaction induces M1 type polarized macrophages to gather, plays a role in clearing accumulated lipid and necrotic cells, and simultaneously releases proinflammatory factors to accelerate inflammation development and plaque formation; with the aggravation of inflammation, M2 type polarized macrophage is activated and releases anti-inflammatory factor, promotes plaque decomposition and plays a role in anti-inflammatory repair. In the research of an atherosclerosis animal model, the activation of M1 polarized macrophages or the inhibition of M2 polarized macrophages can accelerate the formation of atherosclerotic plaques; in contrast, activation of M2 type polarized macrophages can significantly inhibit the development of atherosclerosis. Tissue section analysis of clinical atherosclerosis patients shows that M1 type polarized macrophages are enriched in areas of severe inflammatory plaques with lipid accumulation, and M2 type polarized macrophages are distributed in areas with lower inflammation degree.
Currently, clinical anti-inflammatory treatment strategies for atherosclerosis include the use of traditional anti-inflammatory drugs (e.g., statins, aspirin, etc.), the inhibition of the activity of TNF- α, an inflammation-related factor, an interleukin-like activity (e.g., the monoclonal antibody canakiumab to interleukin IL-1 β), or the inhibition of intracellular inflammation signaling pathway-related molecules, such as the inhibition of the activity of inflammation signaling molecules such as p38MAPK cascade kinase, NADPH oxidase. However, clinical drugs often have the disadvantages of large side effects and low specificity of inflammation inhibition.
Therefore, the method regulates macrophage polarization, targets the generation and development of inflammation and plays a key role in inhibiting the formation of atherosclerosis. The prior art aims at fewer methods for regulating macrophage polarization, but the method for inhibiting inflammation generation and development by regulating macrophage polarization influence is still to be improved and developed, and a more specific and better-effect target regulation method needs to be developed so as to regulate the generation and development of inflammation-related diseases.
Disclosure of Invention
In view of the shortcomings and practical needs of the prior art, the present invention provides a method for regulating macrophage polarization state, which activates cholinergic anti-inflammatory pathway through drug stimulation or electrical stimulation of vagus nerve, and affects the functions of macrophages with different polarization types, thereby inhibiting the occurrence and development of inflammation and inhibiting the formation of atherosclerotic plaque.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a method of modulating the polarization state of macrophages, said method comprising the step of activating the cholinergic anti-inflammatory pathway of the macrophages with a cholinergic anti-inflammatory pathway agonist and/or a vagal electrical stimulation signal.
In the invention, the cholinergic anti-inflammatory pathway agonist is adopted to stimulate macrophages in vitro or an electrical stimulation signal is adopted to stimulate vagus nerve in vivo, so that the activation effect of the cholinergic anti-inflammatory pathway is realized, the polarization of M1 type macrophages is inhibited, and the polarization of M2 type macrophages is promoted.
Preferably, the cholinergic anti-inflammatory pathway agonist comprises an acetylcholine and/or a cholinergic receptor agonist.
Preferably, the cholinergic receptor agonist comprises GTS-21(DMBX-A), a selective alpha 7 nicotinic acetylcholine receptor agonist.
In the invention, acetylcholine or GTS-21 is used as a cholinergic anti-inflammatory pathway agonist to stimulate and activate a cholinergic anti-inflammatory pathway, inhibit the function of M1 type proinflammatory macrophages, promote the function of M2 type proinflammatory macrophages, and have important application in the aspect of specifically regulating polarized macrophage functions and diseases caused by the polarized macrophages.
Preferably, the concentration of acetylcholine is 10-200. mu.M, such as 10. mu.M, 50. mu.M, 100. mu.M or 200. mu.M.
Preferably, the concentration of GTS-21 is 5-50 μ M, for example, 5 μ M, 10 μ M, 20 μ M or 50 μ M.
Preferably, the applied voltage of the vagus nerve electrical stimulation signal is 3-6V, for example, 3V, 4V, 5V or 6V, preferably 5V.
Preferably, the vagus nerve electrical stimulation signal is applied for 1-5 ms, such as 1ms, 2ms, 3ms, 4ms or 5ms, preferably 2 ms.
Preferably, the frequency of the vagus nerve electrical stimulation signal is 1-5 Hz, such as 1Hz, 2Hz, 3Hz, 4Hz or 5Hz, preferably 2 Hz.
In the invention, the electrical stimulation signal stimulates the vagus nerve, activates a cholinergic anti-inflammatory pathway, inhibits the function of M1 type proinflammatory macrophages, and promotes the function of M2 type proinflammatory macrophages.
Preferably, the macrophages comprise RAW264.7 and/or bone marrow derived macrophages.
In a second aspect, the present invention provides a device for regulating a polarization state of macrophages, the device including a cholinergic anti-inflammatory pathway agonist applying unit and/or a vagal electrical stimulation signal applying unit.
Preferably, the cholinergic anti-inflammatory pathway agonist applying unit is for applying acetylcholine and/or GTS-21 to macrophages.
Preferably, the concentration of acetylcholine is 10-200. mu.M, such as 10. mu.M, 50. mu.M, 100. mu.M or 200. mu.M.
Preferably, the concentration of GTS-21 is 5-50 μ M, for example, 5 μ M, 10 μ M, 20 μ M or 50 μ M.
Preferably, the application time is 5-20 min, for example, 5min, 10min, 15min or 20 min.
Preferably, the vagus nerve electrical stimulation signal application unit is for applying an electrical stimulation signal to the vagus nerve.
Preferably, the applied voltage of the electrical stimulation signal is 3-6V, for example, 3V, 4V, 5V or 6V, preferably 5V.
Preferably, the application time of the electrical stimulation signal is 1-5 ms, for example, 1ms, 2ms, 3ms, 4ms or 5ms, preferably 2 ms.
Preferably, the application frequency of the electrical stimulation signal is 1-5 Hz, such as 1Hz, 2Hz, 3Hz, 4Hz or 5Hz, preferably 2 Hz.
In a third aspect, the present invention provides a pharmaceutical composition for modulating the polarization state of macrophages, said pharmaceutical composition comprising a cholinergic anti-inflammatory pathway agonist.
Preferably, the cholinergic anti-inflammatory pathway agonist comprises an acetylcholine and/or a cholinergic receptor agonist.
Preferably, the cholinergic receptor agonist comprises GTS-21.
The pharmaceutical composition further comprises any one or a combination of at least two of pharmaceutically acceptable carriers, excipients or diluents.
The medicinal composition for activating the cholinergic anti-inflammatory pathway has characteristic action, can be introduced into an organism through intravenous injection and transported to a specific part through blood circulation, and achieves the purpose of preventing and treating cardiovascular chronic diseases, gastrointestinal inflammatory diseases, nervous system diseases or malignant tumors.
In a fourth aspect, the present invention provides the use of a device according to the second aspect and/or a pharmaceutical composition according to the third aspect for the manufacture of a medicament for the treatment of a disease associated with inflammation.
Preferably, the disease comprises cardiovascular disease and/or neurological disease.
Preferably, the disease comprises atherosclerosis.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention utilizes acetylcholine or GTS-21 to activate cholinergic anti-inflammatory pathway, inhibit the function of M1 type proinflammatory macrophage and promote the function of M2 type proinflammatory macrophage, thus realizing the effect of specifically regulating polarized macrophage function and diseases caused by the polarized macrophage function;
(2) the invention activates the cholinergic anti-inflammatory pathway by utilizing the electrical stimulation vagus nerve, and has important significance in preventing and treating inflammatory related diseases.
Drawings
FIG. 1 is a technical scheme roadmap;
FIG. 2 is a graph showing that acetylcholine and GTS-21 inhibit the release of proinflammatory factors from M1-type macrophages;
FIG. 3 is a graph showing that acetylcholine and GTS-21 promote M2 type macrophage polarization;
FIG. 4 is a graph showing that GTS-21 activates the cholinergic anti-inflammatory pathway to retard inflammation and plaque formation in atherosclerosis following vagus nerve severance.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
The invention provides a method for regulating the polarization function of macrophages and delaying the development of inflammation by using the technical means of primary cell culture, histopathological observation and the like from the angles of regulating the polarization macrophage function and specifically intervening the inflammatory response, and mainly comprises the following steps: 1) in vitro cell experiments prove that the activation of the cholinergic anti-inflammatory pathway has the regulation effect on macrophage polarization; 2) the inhibition effect of cholinergic anti-inflammatory pathway activation on the inflammatory state of atherosclerosis and aortic plaque is verified by using an atherosclerosis mouse model, and a technical scheme route diagram is shown in figure 1.
Example 1 isolation and culture of bone marrow-derived macrophages
The mice were killed by removing their necks and were sequentially soaked in two 75% alcohol beakers; shearing thigh with scissors, separating femur and tibia, removing skin and flesh, and placing in 10mL RPMI1640 culture medium (containing 10% FBS); cutting off the joint surfaces of the femur and the tibia, exposing a marrow cavity, flushing the marrow cavity by using a 10mL syringe (1mL needle head), and blowing off cells by using a 1mL pipette;
after the cells are filtered by a cell sieve, collecting cell suspension into a 50mL centrifuge tube; centrifuging at 1000g for 8min, discarding supernatant, resuspending cells in 1640 culture medium containing 10ng/mL Macrophage Colony Stimulating Factor (MCSF), inoculating in 6-well plate, and culturing; after three days, medium containing 10ng/mL MCSF was added, and mature bone marrow-derived macrophages (BMDM) obtained after 3 days were cultured.
Example 2 Effect of acetylcholine and cholinergic receptor agonists on M1-type macrophages
Respectively inoculating RAW264.7 or BMDM in a 6-well plate, and adding acetylcholine (0, 10, 50, 100 and 200 mu M) or cholinergic receptor agonist GTS-21(0, 5, 10, 20 and 50 mu M) with different concentrations for treatment for 10min when the cell density reaches about 70%;
m1 macrophage was induced by LPS or IFN γ stimulation, cells were harvested 24h later, and expression of the proinflammatory factors TNF α, IL-1 β, IL-6 was analyzed.
As shown in FIG. 2, in LPS-induced RAW264.7 cells, which were treated with different concentrations of acetylcholine (Ach) and GTS-21 for 24 hours, and then analyzed for the relative expression of proinflammatory factors TNF alpha, IL-1 beta and IL-6, the results showed that the proinflammatory factors induced by LPS can be inhibited by acetylcholine and GTS-21 and exhibit concentration dependence. Similarly, in IFN γ -induced primary bone-derived macrophages, acetylcholine (Ach) and GTS-21 were able to concentration-dependently inhibit the increase of the pro-inflammatory factors TNF α, IL-1 β and IL-6.
Example 3 Effect of acetylcholine and cholinergic receptor agonists on M2-type macrophages
Respectively inoculating RAW264.7 or BMDM in a 6-pore plate, and adding acetylcholine or cholinergic receptor agonist GTS-21 for treatment for 10min when the cell density reaches about 70%;
m2 macrophages were induced by IL-4 stimulation, cells were harvested 24h later, and the expression of the anti-inflammatory factors arginase 1(Arg1), TGF-. beta.and IL-10 was analyzed.
As shown in FIG. 3, in IL 4-induced M2 type macrophage RAW264.7 and primary bone marrow-derived macrophages, acetylcholine (Ach) and GTS-21 can significantly promote differentiation of M2 type macrophages and expression of related marker genes such as Arg1, TGF and IL-10.
Example 4 Effect of GTS-21 or Electrical stimulation on Apoe-/-mouse Atherosclerosis
Feeding Apoe-/-mice with high-fat feed (containing 21% fat and 0.15% cholesterol) for 10 weeks to construct atherosclerosis model mice; after 10 weeks, the unilateral vagus nerve descending from the neck of the mouse and located in the carotid sheath was subjected to a cutting operation;
injecting GTS-21 of 4mg/kg into abdominal cavity of mice once every 3 days, and treating high fat feed Apoe-/-mice;
after the experiment is finished, blood is taken from eyeballs to analyze the expression of serum inflammatory factors, and aorta is separated to analyze vascular plaques.
The present example was also set up with a blank control group, and an equal amount of saline was injected.
The results are shown in fig. 4, and the vagal nerve cutting obviously promotes the generation of serum inflammatory factors TNF alpha and IL-6 and promotes the formation of arterial plaque; and the GTS-21 treatment after cutting off vagus nerve can obviously inhibit the generation of serum inflammatory factors TNF alpha and IL-6 and slow down the formation of atherosclerotic plaques.
The vagus nerve of an atherosclerosis model mouse is stimulated by an electrical stimulation signal (5V, 2ms and 2Hz), the expression of serum proinflammatory factors TNF alpha, IL-1 beta and IL-6 is found to be inhibited, and the expression of anti-inflammatory factors TGF and IL-10 is improved, so that the electrical stimulation of the vagus nerve also realizes the regulation of the polarization state of macrophages, namely the polarization of M1 type macrophages is inhibited, the differentiation of M2 type macrophages is promoted, and the formation of atherosclerotic plaques is slowed down.
In conclusion, the invention activates the cholinergic anti-inflammatory pathway through drug stimulation or electrical stimulation on the vagus nerve to influence the functions of macrophages with different polarization types, thereby inhibiting the generation and the development of inflammation and having important significance in the prevention and the treatment of inflammatory diseases.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A method of modulating the polarization state of macrophages, comprising the step of activating the cholinergic anti-inflammatory pathway of the macrophages with a cholinergic anti-inflammatory pathway agonist and/or a vagal electrical stimulation signal.
2. The method of claim 1, wherein the cholinergic anti-inflammatory pathway agonist comprises an acetylcholine and/or a cholinergic receptor agonist;
preferably, the cholinergic receptor agonist comprises GTS-21;
preferably, the concentration of the acetylcholine is 10-200 mu M;
preferably, the concentration of the GTS-21 is 5-50 mu M.
3. The method according to claim 1, wherein the applied voltage of the vagus nerve electrical stimulation signal is 3-6V;
preferably, the application time of the vagus nerve electrical stimulation signal is 1-5 ms;
preferably, the application frequency of the vagus nerve electrical stimulation signal is 1-5 Hz.
4. The method of any one of claims 1-3, wherein the macrophages comprise RAW264.7 and/or bone marrow derived macrophages.
5. A device for regulating a polarization state of macrophages, comprising a cholinergic anti-inflammatory pathway agonist applying unit and/or a vagal electrical stimulation signal applying unit.
6. The apparatus according to claim 5, wherein the cholinergic anti-inflammatory pathway agonist applying unit is for applying acetylcholine and/or GTS-21 to macrophage;
preferably, the concentration of the acetylcholine is 10-200 mu M;
preferably, the concentration of the GTS-21 is 5-50 mu M;
preferably, the application time is 5-20 min.
7. The apparatus according to claim 5, wherein the vagus nerve electrical stimulation signal applying unit is configured to apply an electrical stimulation signal to the vagus nerve;
preferably, the applied voltage of the electric stimulation signal is 3-6V;
preferably, the application time of the electric stimulation signal is 1-5 ms;
preferably, the application frequency of the electric stimulation signal is 1-5 Hz.
8. A pharmaceutical composition for modulating the polarization state of macrophages, comprising a cholinergic anti-inflammatory pathway agonist;
preferably, the cholinergic anti-inflammatory pathway agonist comprises an acetylcholine and/or a cholinergic receptor agonist;
preferably, the cholinergic receptor agonist comprises GTS-21.
9. The pharmaceutical composition of claim 8, further comprising any one or a combination of at least two of a pharmaceutically acceptable carrier, excipient, or diluent.
10. Use of a device according to any one of claims 5 to 7 and/or a pharmaceutical composition according to claim 8 or 9 for the manufacture of a medicament for the treatment of a disease associated with inflammation;
preferably, the disease comprises any one of cardiovascular disease, sepsis, rheumatoid arthritis, nervous system disease or tumor or the combination of at least two of the above;
preferably, the disease comprises atherosclerosis.
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| CN113897337A (en) * | 2021-05-31 | 2022-01-07 | 中国科学院深圳先进技术研究院 | Method for regulating polarization state of macrophage |
| WO2022252097A1 (en) * | 2021-05-31 | 2022-12-08 | 中国科学院深圳先进技术研究院 | Method for adjusting polarization state of macrophages |
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| CN1735414A (en) * | 2002-12-06 | 2006-02-15 | 北岸长岛犹太人研究学院 | Inhibition of inflamation using alpha 7 receptor-binding cholinergic agonists |
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| US8914114B2 (en) * | 2000-05-23 | 2014-12-16 | The Feinstein Institute For Medical Research | Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation |
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| CN113897337A (en) * | 2021-05-31 | 2022-01-07 | 中国科学院深圳先进技术研究院 | Method for regulating polarization state of macrophage |
| WO2022252097A1 (en) * | 2021-05-31 | 2022-12-08 | 中国科学院深圳先进技术研究院 | Method for adjusting polarization state of macrophages |
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