The role of Interleukin-1 family in cardiovascular disease and its research progress

Lin Heng-xiu, Zhang Yuan-yuan, Zhang Bin-yue, Wu Yue-wei, Li Tian-fa?

1.Department of Cardiovascular Medicine, The First Affiliated Hospital of Hainan Medical College, Haikou 570100, China

2.Hainan Medical College, Haikou 570100, China.

Keywords:

ABSTRACT The interleukin-1 family is a group of important cytokines that play a key regulatory role in the immune and inflammatory response (including infectious and non-bacterial injuries).Nowadays, the interleukin-1 family mainly includes 11 cytokines and has multiple roles in the pathology and physiology of inflammation.Moreover, accumulating number of research show that the interleukin-1 family and its receptors are involved in the occurrence and development of cardiovascular diseases.Therefore, we show here the review involving hotspots of the interleukin-1 family in the process of inflammation and its target therapy in cardiovascular diseases, including atherosclerosis, myocardial infarction and heart failure.

Cardiovascular disease (CVD) is one of the main causes of death in the world[1].According to the “China Cardiovascular Health and Disease Report 2020”, the number of CVD patients in my country is about 330 million, which is the leading cause of death among Chinese citizens.primary cause[2].The etiology of CVD is complex, and it is currently believed that CVD is inseparable from the inflammatory response.Interleukin-1 ( IL-1) family cytokines are important mediators of inflammatory responses.A large number of research data show that IL-1 family members and their receptors are involved in the occurrence and development of CVD.Regulation of IL-1 family cytokines can reduce the progression of CVD.Currently, there are biological agents that block the effect of IL-1[3], but there are many IL-1 family cytokines, and the clinical IL-1 family members There are very few blockers.The role of IL-1 family cytokines in CVD still needs further research by scholars.

1.Overview of the IL-1 family

IL-1 family cytokines are important mediators of inflammatory responses.IL-1 family cytokines are divided into three subfamilies according to the number of amino acids at the C-terminus of the fulllength amino acid sequence of IL-1 family cytokines (as shown in Figure 1).Except for IL-α, which can directly play an active role,other family members are It needs to be expressed as a precursor,and then processed into an active molecule by caspase-1 hydrolysis to play the corresponding effect[4-5].Current studies have found that there are 11 cytokines in this family, including pro-inflammatory factors and anti-inflammatory factors.IL-36γ, the corresponding receptor antagonists are IL-1 receptor antagonist (IL-1Ra), IL-36 receptor antagonist (IL-36Ra), IL-38, anti-inflammatory factor has IL-37.Among the IL-1 family cytokines, IL-1α and IL-1β are more biologically active[6].As an inflammatory factor, IL-1αnot only has the function of local contact with cell surface receptors, but also directly regulates the expression of inflammatory genes through nuclear localization and binding to specific sites in the nucleus, such as the nitrogen-terminal amino acid sequence[7].IL-1β is a classic pro-inflammatory cytokine.After the inflammasome activates Tolllike receptors, inflammatory cells will accumulate and release IL-1β precursors, which are cleaved by Caspase-1 to form IL-1β to play a role in promoting inflammation.role[8].Both IL-1α and IL-1β induce local inflammation and the recruitment and activation of neutrophils, monocytes, and macrophages, which contribute to inflammation[9].Both IL-1α and IL-1β can be competitively bound to IL-1 receptor ( IL-1R) by IL-1Ra and inhibit its activity[4].IL-33 can cause and regulate the formation of heterodimeric complexes by affecting Suppression of tumorigenicity (ST2) and the corresponding IL-1 Receptor Accessory Protein (IL-1R1AcP)A variety of inflammatory responses[5].IL-18 can synergize with IL-12 or IL-15 to induce type 1 T helper (Th1) cells to produce interferon-γ to mediate inflammatory responses, and it can also activate Th17 cells to produce IL-17 to promote tissue Inflammation and damage necrosis.However, in the absence of IL-12 and IL-15,IL-18 induces a Th2 response and inhibits inflammation [10].IL-37 plays an anti-inflammatory role by inhibiting the secretion of proinflammatory cytokines such as IL-1β and IL-6 and enhancing the expression of CD206 and IL-10[11].Like other IL-1 family members,IL-36α, β, and γ all require proteolytic enzymes for activation,and neutrophil-derived cathepsin G, elastase, and protease-3 have recently been shown to play a role in IL-36 cytokines.play an important role in the processing and activation[12].Activated IL-36α, β and γ specifically bind to IL-1 receptor-related protein 2(IL-1Rrp2) through the IL-1 family receptor member IL-1R1AcP and are affected by IL-1Rrp2.-36Ra regulation[13].

2.The relationship between IL-1 family and cardiovascular disease

2.1 IL-1 family and atherosclerosis

Atherosclerosis (AS) is a chronic inflammatory disease, and inflammation has been shown to play an important role in the formation and development of atherosclerotic plaques[14].IL-1 family cytokines, as important members of cytokines, can connect to Toll-like receptors or scavenger receptors (such as CD36) to increase the expression and activation of IL-1α, IL-1β and IL-18.IL-1α can promote the expression of vascular cell adhesion molecule-1 on endothelial cells and mediate the subendothelial migration of leukocytes, which is an important step in the formation of atherosclerosis.Schunk et al found that compared with wild-type mice, IL-1α gene (IL-1 -/-) knockout mice had significantly reduced leukocyte-endothelial cell adhesion, while IL-1β gene (IL-1β- /-)This was not observed in knockout mice[15].IL-1β promotes the development of chronic inflammatory diseases and the formation of atherosclerosis by (1) inducing monocytes and fibroblasts to produce pro-inflammatory factor IL-6 and inducing Th17 cells to produce cytokines; (2) promoting intimal endothelial cells The expression of adhesion molecules and chemokines to mediate atherosclerotic effects; ③ induce the production of platelet-derived growth factor that stimulates vascular smooth muscle cells; ④ induce oxidative stress, stimulate the production of prostaglandins, and constrict blood vessels Activate platelets.Further aggravate atherosclerosis and thrombosis[6,16-17].Ceneri et al.found that the expression level of IL-1β was significantly increased in the aorta and human coronary plaques of ApoE -/- mice[18].

Compared with stable plaques, IL-18 gene expression levels were significantly increased in unstable plaques.IL-18 induces abnormal activation of IFN-γ expression in Th1 cells during the formation of atherosclerotic plaques, and IL-18 and IL-18 receptors are also highly expressed on human atherosclerosis-related cells.However, in the absence of Th1 cells and IL-18 receptors, IL-18 can also mediate and affect the formation of atherosclerosis in apolipoprotein E genedeficient mice (Apoe-/-).Analysis of relevant clinical data It has also been confirmed that high levels of IL-18 expression in human serum are positively correlated with CVD risk [19].However, a recent Meta-analysis showed that the correlation between IL-18 levels and the risk of CVD remains to be further explored[20].IL-1α, IL-1β and IL-18 play an important role in AS.Although some scholars have doubts about the relationship between IL-18 and CVD, most scholars believe that the existence of IL-1 family of inflammatory factors and Increased levels can promote the occurrence and aggravate the development of atherosclerosis.

2.2 IL-1 family and acute myocardial infarction

The pathogenesis of acute myocardial infarction (AMI) is mainly due to the rupture and hemorrhage of unstable coronary plaques,inducing acute thrombosis, and causing partial or complete occlusion of the coronary arteries.A large body of evidence suggests that inflammatory responses play an important role in atherosclerotic plaque formation and plaque instability[21].Acute inflammatory injury to the myocardium is characterized by activation of the inflammasome and release of IL-1β and other proinflammatory cytokines.IL-1β can further aggravate the death of cardiomyocytes and mediate ventricular structural changes and dysfunction in AMI[22].In a mouse model, Bujak et al.demonstrated that inhibition of IL-1R1 gene expression attenuated MI-induced myocardial injury, and correspondingly, overexpression of IL-1Ra reduced cardiomyocyte apoptosis and protected myocardium from ischemic injury[23], thereby confirming the deleterious role of IL-1β in the inflammatory process after myocardial injury.Woldbaek et al.found that in the mouse myocardial infarction model, the expression and serum concentration of IL-18 in cardiac tissue and mouse plasma were significantly increased compared with the control group.Using IL-18 antibody or recombinant IL-18-binding protein (IL-18BP) ) blocking IL-18 can alleviate myocardial injury induced by MI to a certain extent in mice[24-25].In addition, studies have shown that compared with control mice, the IL-1 family cytokine cleaving enzyme Caspase-1 gene knockout (Caspase-1-/-) mice have significantly reduced myocardial infarction size, and found that inhibition of Caspase The expression of -1 gene can significantly improve the inflammatory response after myocardial ischemiareperfusion injury[26].Although there is still disagreement in the industry on the role of IL-1 family cytokines in the pathological process of myocardial infarction, it is certain that IL-1 family inflammatory cytokines are abnormally activated after myocardial infarction.It is believed that IL-1 family cytokines play an important role in myocardial injury and deterioration of cardiac function after AMI.

2.3 IL-1 family and heart failure

Heart failure is the end stage of CVD development, and ischemic cardiomyopathy is the most common cause of heart failure[27].It has been reported that elevated levels of proinflammatory cytokines in patients with heart failure often correlate with disease severity[28].Studies have shown that IL-1 family members may play an important role in the progression of heart failure and the pathogenesis of systolic dysfunction[27-28].Although the mechanisms by which IL-1α and IL-1β are produced by cells are different, they have similar roles in heart failure.At present, the accepted mechanisms of IL-1α and IL-1β-mediated heart failure are as follows: ① IL-1R1/IL-1RAcP promotes inflammation by recruiting multiple intermediate proteins to activate IL-1R-related kinases and tumor necrosis factor receptor-related factor-6; ②IL-1 induces myocardial uncoupling by inhibiting L-type calcium channels and β-adrenergic receptors Impaired contractile function; ③ IL-1β increases nitric oxide activity by activating nitric oxide synthase, and affects mitochondria to play normal physiological functions by mediating calcium and β-AR signaling pathways; ④ Inducing leukocyte mobilization and activation, thereby stimulating downstream Inflammatory response[29].In addition to IL-1, IL-18 is abnormally highly expressed in the heart tissue of patients with heart failure, and IL-18 is involved in and regulates the formation of myocardial dysfunction and fibrosis in a mouse model of myocardial hypertrophy[30-31].Relevant studies have shown that in addition to the direct myocardial injury effect in the myocardial ischemia-reperfusion model, Caspase-1 has a longterm regulatory role in the process of promoting cardiomyocyte apoptosis, and is involved in mediating and promoting the formation of heart failure[32-33].In addition, IL-33 plays an important role in myocardial injury repair, but when it binds to soluble ST2(sST2), it inhibits the beneficial remodeling of cardiomyocytes and exacerbates the development of acute heart failure in decompensated stages[34].IL-1 family cytokines not only affect the occurrence of atherosclerosis and myocardial infarction, but also affect the prognosis of myocardial infarction, aggravate myocardial fibrosis and adverse cardiac remodeling after myocardial infarction, and aggravate the occurrence of heart failure.

2.4 IL-1 family and other cardiovascular diseases

IL-1 family cytokines are also closely related to the occurrence and development of myocarditis, structural heart disease, hypertrophic cardiomyopathy and other diseases[35-39].Recently, Zhang et al.found that in a RAS-activated mouse model of hypertension, IL-1 was highly expressed after the recruitment of macrophages in the kidney tissue: blocking IL-1R1 could control the increase in blood pressure[40].Johnston et al.also reported that IL-1β deficiency or the addition of adenylate to block IL-1R1 attenuated the pathological formation of abdominal aortic aneurysms in mice[41].IL-1β can also affect the course of myocarditis and induce the possibility of arrhythmia[6].

3.IL-1 family target therapy

The IL-1 family affects the occurrence and development of CVD by regulating inflammation, and blocking the pro-inflammatory effect of IL-1 family factors can delay the course of CVD to a certain extent[42].Three IL-1 blockers with different mechanisms of action have been approved for clinical use, namely Canakinumab, Anakinra and Rilonacept.Canakinumab is primarily approved for the treatment of immune-inflammatory diseases such as Still’s disease,acute gouty arthritis, and colchicine-resistant familial Mediterranean fever in adults[43-48].Anakinra is currently used for the treatment of diseases such as recurrent pericarditis, rheumatoid arthritis,cryomorph-associated periodic syndrome (CAPS), Still's disease,and pediatric secondary hemophagocytic lymphohistiocytosis[49-52].Rilonacept has also recently been approved for the treatment of recurrent pericarditis[53].

Canakinumab is a monoclonal antibody that neutralizes IL-1β.The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) study found that in 10,061 subjects, compared with placebo, patients treated with 150 mg of canakinumab developed myocardial The primary endpoint of infarction or cardiovascular death was reduced by 15%, and the 150 mg canakinumab group was also found to reduce the incidence of coronary revascularization and significantly reduce all-cause mortality from cardiovascular disease.In addition, in patients treated with canakinumab for 4 years, the high-sensitivity-C-reactive protein in the experimental group was reduced by 26%-41% compared with the placebo group, and the incidence of cardiovascular events was also significantly reduced [54-55].The above studies suggest that canakinumab treatment reduces inflammation and the incidence of major cardiovascular events, and also provides experimental evidence for the role of IL-1 in mediating thrombosis in atherosclerotic processes.Although Canakinumab has not yet been approved for the clinical treatment of CVD, with further research on it, Canakinumab is expected to become a new drug for the treatment of CVD in the future.

Anakinra is a recombinant human IL-1 receptor antagonist that competitively blocks the biological effects of IL-1α and IL-1β.A phase II clinical drug trial of Anakinra at Virginia Commonwealth University showed that in patients with acute ST segment elevation myocardial infarction (STEMI), the experimental group significantly reduced acute inflammatory markers, and the incidence of heart failure and Hospitalization rates were significantly reduced[56].Similarly, Marco et al.also found that the use of Anakinra in STEMI patients significantly accelerated the regression of increased white blood cell counts and neutrophil counts compared with placebo,suggesting that Anakinra can improve the prognosis of AMI[57].In a study of acute decompensated heart failure, patients treated with Anakinra had greater declines in C-reactive protein and faster recovery of left ventricular ejection fraction than controls[58].Anakinra has demonstrated significant efficacy in acute and chronic pericarditis in the AIRTRIP trial and in clinical trials by Imazio M et al[59-60].Anakinra has been established by the European Society of Cardiology as the third-line treatment option for refractory recurrent pericarditis (RP), and is currently the drug of choice for the treatment of RP after failure of conventional anti-inflammatory therapy,including non-steroidal anti-inflammatory drugs[61].Although Anakinra is only approved for the treatment of RP in CVD, it has achieved significant efficacy in clinical trials of AMI and acute heart failure, and may be used in clinical treatment of AMI and acute heart failure in the future.

Compared with the first two target drugs, the current clinical research data on Rilonacept mainly focus on RP.Rilonacept, a recombinant dimeric fusion protein that blocks IL-1R1 binding by binding to IL-1α and IL-1β, is now a valuable therapeutic option for RP.In a phase 3 clinical trial for the treatment of RP, Allan et al.conducted a 12-week study of placebo or Rilonacept in 86 patients with RP and elevated C-reactive protein levels.The results showed that Rilonacept can rapidly Relieve RP attacks and significantly reduce the recurrence rate of RP[3].Recently, Rilonacept was approved by the US Food and Drug Administration (FDA) for clinical treatment of RP[62].

In addition to the above-mentioned targeted drugs that have been approved for clinical blockade of IL-1, there are still some targeted drugs in the stage of animal experiments.Although these factor treatments have not been approved for clinical use, there are a large number of animal experimental data to support, provides a new treatment modality for myocardial reperfusion-injury.In a mouse model, after knocking out the mouse IL-1R1 gene and using recombinant IL-1Ra or monoclonal antibody to neutralize IL-1α,Mauro et al.found that the infarct size of AMI in the mouse IL-1R1 gene-deficient group was higher than that in the control group.significantly less[63-64].Zhu et al found that administration of recombinant human IL-1 receptor antagonist after AMI reperfusion in mice reduced myocardial ischemia-reperfusion injury in mice[65].In addition, Yin et al.performed rescue experiments with exogenous IL-33 during acute myocardial infarction in mice and found that IL-33 reduced myocardial infarct size and effectively inhibited ventricular remodeling by binding to trans-model ST2(ST2L)[66].Guo et al.found that anti-IL-1β treatment could delay the development of thoracic aortic dissection in rats and reduce the mortality of rats[67].The above experiments have confirmed the drug target value of IL-1 family factors.

4.Outlook

Today, a large number of clinical research data have confirmed that IL-1 family cytokines can participate in the occurrence and development of CVD such as atherosclerosis, myocardial infarction,heart failure, and pericarditis by mediating vascular inflammation.A total of 11 cytokines have been found in the IL-1 family.Among them, IL-1 is particularly closely related to CVD.Blocking the pro-inflammatory effects of IL-1 family factors may slow the development of CVD.There are three IL-1 blockers with different mechanisms of action in clinical use.Anakinrah and Rilonacept have been approved for the treatment of recurrent pericarditis, but they are also used in the treatment of other CVDs such as atherosclerosis,acute myocardial infarction, and heart failure.It shows that in addition to good effects, it is expected that the scope of its clinical application in the future will be much larger than expected.The treatment of canakinumab in atherosclerosis and thrombosis is also in the final clinical trial stage, and the significant effect on CVD treatment is also worthy of our attention.At present, the pathogenesis of IL-1 family factors in CVD is not completely clear, and its role and potential in CVD treatment still need the support of a large number of experimental data and the continuous in-depth research of scholars.IL-1 target therapy will become the future of CVD.Research hotspots of precision therapy.

Authors' contribution

The first author: Lin Heng-xiu: collect relevant literature and write papers; Corresponding author: Li Tian-fa: article project conception and review; Zhang Yuan-yuan, Zhang Bin-yue, Wu Yue-wei:participate in literature collection and analysis.

All authors declare no conflict of interest.