Friend or foe of innate lymphoid cells in inflammation‐associated cardiovascular disease

Short abstract

Following cardiac injury, IL‐33 produced by fibroblast promoted ILCs and macrophages showing the type II immune phenotype to ameliorate inflammation; in pericardial fluid, IL‐5 and IL‐13 secreted by activated ILC2s led to cardiac fibroblasts to produce a large number of eotaxin; furthermore, the production of IL‐1β by cardiac macrophages may promote ILCs differentiation into ILC3s.

Summary

As a distinctive population of leucocytes, innate lymphoid cells (ILCs) participate in immune‐mediated diseases and play crucial roles in tissue remodelling after injury. ILC lineages can be divided into helper ILCs and cytotoxic ILCs. Most helper ILCs are integrated into the fabric of tissues and produce different types of cytokines involving in the pathogenesis of many kinds of cardiovascular disease and form intricate response circuits with adaptive immune cells. However, the specific phenotype and function of helper ILC subsets in cardiovascular diseases are still poorly understood. In this review, we firstly highlight the distribution of helper ILCs in cardiovascular system and further discuss the potential contribution of helper ILCs in inflammation‐associated cardiovascular disease.

Abbreviations

AT

adipose tissue

CVD

cardiovascular diseases

EGPA

eosinophilic granulomatosis with polyangiitis

ILCs

innate lymphoid cells

LTi

lymphoid tissue‐induced cells

MI

myocardial infarction

INTRODUCTION

Cardiovascular diseases (CVD) are the leading cause of global mortality and incidence rate in non‐communicable diseases. Many factors can lead to the occurrence of CVD, although its pathogenesis remains ulcear. ¹ The role of inflammation in CVD has been widely accepted in the initial and progression. B and T cells are involved in promoting the production of antibodies and inflammatory factors, such as IFN‐γ, TNF‐α, and IL‐17A, leading to sustain damage to the cardiovascular system. ² IFN‐γ and TNF‐α have been reported as proatherogenic cytokines in vascular diseases, and IL‐17A aggravates cardiac damage, promoting fibrosis. ³ , ⁴ Therefore, whether in clinical or experimental data, the modulation of adaptive immune cells has already been thoroughly studied, and it is of great help for the prevention and treatment of CVD. However, it is worth noting that more and more researchers have discovered that the innate immune plays an important role in the pathogenesis of CVD. Previous studies have found that the primary innate immune cells within cardiac tissue are mainly macrophages, including tissue‐resident macrophages and monocyte‐derived macrophages, contributing to cardiac tissue injury and repair. ⁵ Other innate immune cells such as mast cells and dendritic cells also found sparsely distributed in cardiac tissue. ⁶ , ⁷ Beyond innate immune cells given here, innate lymphoid cells (ILCs) are newly discovered innate immune cell subset in recent years; however, their specific role in CVD is still unclear.

ILCs mainly include cytotoxic ILCs and helper ILCs. ILCs mostly located on the barrier surface of the body, respond to environmental stress signals and participate in the protection of pathogens, tissue remodelling and maintenance of internal balance and promote the formation of secondary lymphoid organs with the interaction of mesenchymal cells during embryonic development. ⁸ , ⁹ , ¹⁰ , ¹¹ This review will discuss the distribution of ILCs in the cardiovascular system, the regulation of its response and its roles in physiological and pathophysiological processes.

INNATE LYMPHOID CELLS

According to whether there is the inhibitor of DNA binding 2 (ID2) expression, innate lymphoid progenitor, the progeny of common lymphoid progenitor which could differentiate into almost all types of lymphocytes, mainly divided into two ILC lineages: helper ILCs and cytotoxic ILCs. ¹² , ¹³ , ¹⁴ Moreover, common helper ILC progenitor whether with the existence of PLZF could give rise to ILC precursors, and lymphoid tissue inducer progenitors, which differentiate into lymphoid tissue‐induced cells (LTi). ¹³ , ¹⁵ NKs are cytotoxic ILCs, which are analogous to CD8⁺ T cells. NKs, circulating in the bloodstream, with the ability to secrete pro‐inflammatory cytokines like TNF‐α and IFN‐γ, are the first line of eliminating virus‐infected cells through two major pathway, including target cell death pathway and death receptor pathways (FasL and TRAIL) induced by the production of perforin and granzyme. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ Helper ILCs are categorized into several subsets, which resemble in CD4⁺ T cells subsets (Th1, Th2, Th17), including LTi, ILC1, ILC2 and ILC3, which is based on the ranks of categorization of signature cytokines, transcription factors and so on. ²⁰ Like adaptive lymphocytes, ILCs respond specifically to different immune responses through secreting distinct cytokines. The development of ILCs relies on the IL‐2Rγc and IL‐7Rα, whereas lack of recombinant activating gene and as a result, they do not exhibit antigen specificity. ⁸ , ²¹

ILC1s are characterized by their ability to produce IFN‐γ and TNF‐α, which depend on T‐bet and not on eomesodermin (Eomes). ²² Similar to NKs, ILC1s that respond to IL‐12, IL‐15 and IL‐18 can participate in the first line of defence against viral and certain parasite infections such as T. gondii ²³ or C. difficile ²⁴ . ILC1s were originally distinguished from NKs because of their lower cytotoxic activity, whereas they are also capable of recognizing and killing target cells, although less efficiently. ²⁵ , ²⁶ ILC1s are heterogeneous and have different phenotypic markers, which express CD127 and CD200R in humans, ²⁷ and express NKp46 in both mice and humans, depending on the microenvironment of the tissue. ILC2s are tissue‐resident and express GATA3. ²⁸ , ²⁹ , ³⁰ , ³¹ ILC2s can produce Th2‐associated cytokines, such as IL‐4, IL‐5, IL‐9, IL‐13, the epidermal growth factor amphiregulin with the responses to IL‐25, IL‐33 and thymic stromal lymphopoietin. ³² , ³³ , ³⁴ ILC3s depend on RORγt, encoded by RORC related to retinoic acid receptor for their development and function, which is characterized by the production of IL‐17, IL‐22 and GM‐CSF. ³⁵ ILC3s have at least two subsets and every subset is quite different in transcription, development and function, and locate in different tissue microenvironments. ILC3 subsets are distinguished according to the expression of natural cytotoxic receptor NKp46 (also known as NCR1 in mice or NCR2 in humans). ³⁶ , ³⁷ IL‐22 predominantly produced by NCR⁺ ILC3, whereas IL‐17 mainly derived from NCR⁻ ILC3. ³⁸ Additionally, Th17 cells can also be regulated by ILC3s. ³⁹ LTi cells are a population identified earlier than other ILC subsets. ⁴⁰ Although LTi cells can secrete IL‐17, IL‐22 and lymphotoxin with expressing RORγt, they are different from ILC3s in the development of precursor cells. ⁴¹ , ⁴² Lymph nodes and Peyer's patches require LTi to express surface lymphotoxin α1β2, which can bind to its receptor LTβR on stromal cells during the fetal stage to promote their formation and development, ⁴³ , ⁴⁴ , ⁴⁵ whereas adult LTi‐like cells protect the gastrointestinal tract from pathogens by producing IL‐17 and IL‐22, ⁴⁶ , ⁴⁷ , ⁴⁸ and can also express OX40L and CD30L, which both are T‐cell survival molecules, indicating that they may affect T‐cell function. ⁴⁹ , ⁵⁰

Recently, ILCs have already been studied in various tissues and organs, especially in mucosal tissues. ⁵¹ , ⁵² They can effectively participate in the regulation of tissue microenvironment in both homeostasis and inflammation conditions. Although the helper ILCs have been extensively reported in barrier organs, there are few studies on their roles in cardiovascular system. ⁵³ NKs, as a protector, prevent cardiac inflammation and injury in most CVDs; however, more and more studies suggested that they promote inflammation in atherogenesis. ⁵⁴ , ⁵⁵ , ⁵⁶ The characteristics of NKs in CVD have been well reviewed elsewhere ⁵⁴ , ⁵⁷ and therefore not be discussed here.

ILCs IN CARDIOVASCULAR SYSTEM

The heart is not homogeneous with the unique histological characteristics so that the distribution of immune cells in the heart is not uniform, which is quite different from the tissue previously studied by ILCs. In healthy adult mice, it contains almost all major white blood cell types, including monocyte phagocytic cells, neutrophils, T and B cells. ⁵⁸ Recent data have shown that high proportion of cell population characterized by lineage^negCD45⁺CD127⁺RORγt⁻T‐bet⁻CRTH2⁻ and lineage^negCD45⁺CD90⁺RORγt⁻T‐bet⁻CRTH2⁻ are present in the heart of human and naïve mouse, respectively ⁵⁹ (lineage‐negative cell is the rest of cell in which mature cell lineage markers were not expressed, including T, B cells, monocytes/macrophages, granulocytes, NK cells and erythrocytes markers). These cell populations do not have specific markers of ILC subsets, so they are considered as undifferentiated ILCs in the normal heart. ⁵⁹ , ⁶⁰ The heart lacks typical epithelial cells, mainly muscle tissue. The surface of the heart is covered with a membranous structure called the pericardium, which is mainly composed of the epicardium, pericardial cavity, parietal layer of serous and fibrous layer. ⁶¹ Under steady state, serous cavities with the protective serosal fluid harbour large numbers of immune cells, such as macrophages, B cells and so on, and as a result, it may be one of a source of tissue‐infiltrating leucocytes during pathological conditions. ⁶² , ⁶³ Pericardial adipose tissue (AT) is an abundant source of leucocytes, such as B, T, dendritic cells and myeloid cells. ⁶⁴ ILCs may also exist in AT under normal conditions. It has been reported that ILC2s reside in the visceral AT‐secreting IL‐5 and IL‐13 following IL‐33 stimulation, and promote the accumulation of alternatively activated macrophages and eosinophils. Besides IL‐4 secreted by eosinophils co‐operate with ILC2s‐derived IL‐13 to activate IL‐4 receptor signalling in PDGFRα⁺ adipocyte precursors to control beige fat biogenesis. ⁶⁵ , ⁶⁶ , ⁶⁷ Moreover, ILC1s, which indicated as a stable population in AT to produce IFN‐γ, can suppress ILC2s activation, thereby restraining the accumulation of Treg cells. ⁶⁸ ILC1s also contribute to promote obesity‐associated insulin resistance and polarize macrophages towards M1 macrophages by expressing IFN‐γ. ⁶⁹ , ⁷⁰ There are initial indications that ILCs with progenitor‐like features have cardiac specific feature, ⁵⁹ which is worth further investigation.

The intima of the artery is the layer between the arterial endothelium and the first elastic layer of the artery, such that the intima is on top of the medial layer that is rich in smooth muscle cells and outer layers of arteries, known as the adventitia. Anatomically and histologically, the intimal layer is the main area of chronic inflammatory development, which is the characteristic of atherosclerosis, and eventually caused the corresponding tissue of the vascular supply to ischaemia or necrosis. ⁷¹ The pathological lesion in the arterial intima continuously accumulates and increases the size of the intima under the influence of inflammatory factors, forming an inflammatory structure called plaque where contains a lot of inflammatory cells. In human plaques, T cells account for about 10%, of which 70% are regarded as CD4⁺ T cells, and the others largely CD8⁺ T cells. ⁷² Most CD4⁺ T cells in the vessel wall are Th1 cells, which promote the development of atherosclerosis by producing TNF‐α and IFN‐γ. Other T‐cell subsets also have been addressed in plaques, such as Th2, regulatory Th17 cells, NKT cells and so on. ⁷³ In the ‘pre‐ILC‐era’, many studies’ primary aim is to study T‐cell responses in vascular diseases. However, it is worth noting that the lesion size cannot be significantly affected in the Ldlr^−/−Rag1^−/− mice, which are depleted the ILCs globally by anti‐CD90.2, whereas each subset of ILCs has divergent effects on atherosclerosis ⁷⁴ (see below).

HELPER ILCs IN CARDIOVASCULAR DISEASE

Helper ILCs in cardiac inflammation

Myocarditis is caused by infectious agents including viruses, bacteria, protozoa and non‐infectious agents, which have the characteristics of leucocyte infiltration, myocardial oedema and fibrosis. ⁷⁵ The viral infection is the most common cause of myocarditis. The development of viral myocarditis is related to autoimmune diseases. ⁷⁶ If the disease cannot be recovered, it will convert into dilated cardiomyopathy. ⁵⁸ The cardiac ILC is a static, phenotypic undifferentiated population; in physiologic conditions, ILCs do not have specific subset and immunophenotypes, although flow cytometry revealed that they are all characterized as CD45⁺Lin⁻CD127⁺ cells, and activated cardiac ILCs are characterized by transient co‐expression of Ki67 and PLZF in vitro. As described for ILC progenitors, while the inflammatory processes, the cardiac ILCs will develop ILC type 2 characteristics as a pathogenic role in promoting cardiac inflammation ¹⁴ , ⁵⁹ , ⁷⁷ (Figure 1).

Figure 1.

The role of the helper ILCs in inflammatory cardiac disease. Cardiac ILCs lack of specific markers of helper ILCs. In the inflammatory phase, CD29⁺ Sca‐1⁺ cardiac fibroblasts secrete IL‐33, which makes the cardiac ILCs transform into the cytokines produced nILC2s, and macrophages transform into anti‐inflammatory M2 type, to alleviate the cardiac inflammation. In pericardial fluid, activated ILC2s produce IL‐5 and IL‐13, which leads to cardiac fibroblasts to produce a large number of eotaxin, as well as the accumulation of eosinophils in heart. The production of IL‐1β by cardiac macrophages may promote the transformation of ILCs into ILC3s.

It has been demonstrated that there are two subsets of ILC2s, one of which is the ‘homeostatic or natural ILC2 cells’ (nILC2 cells, Lin⁻IL‐7Rα⁺Thy‐1^hiST2⁺KLRG1^int) stimulated by IL‐33, and the other is the IL‐25‐responsive ILC2 cells defined as ‘inflammatory ILC2 cells’ (iILC2 cells, Lin⁻ IL‐7Rα⁺ Thy‐1^loST2⁻KLRG1^hi). ⁷⁸ , ⁷⁹ Not all organs and tissue have two types of ILC2s, and in experimental autoimmune myocarditis, cardiac ILCs cannot be differentiated into iILC2 for lacking IL‐25 receptor. ⁵⁹ The activation and amplification for ILC2s through the IL‐33 have been demonstrated. ⁶² , ⁸⁰ , ⁸¹ IL‐33 is involved in relieving cardiac hypertrophy induced by the transverse aortic constriction in mouse and has antihypertrophic and antifibrotic effects in myocardial infarction (MI) mouse model, which is a kind of myocardial necrosis caused by myocardial ischaemia and anoxia after coronary artery occlusion thrombosis. ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ IL‐33 can induce cardiac ST2L⁺CD4⁺T cells and ST2L⁺ macrophages to express IL‐4. IL‐4 offers the opportunity to induce macrophages into M2 macrophages and to promote the proliferation and accumulation of ILC2s, which play a protective role in viral myocarditis. ⁸⁶ , ⁸⁷ Additionally, Th2 differentiation relies on IL‐4‐mediated STAT6 signalling, providing the possibility that ILC2‐derived IL‐4 induced by IL‐33 might contribute as an initial source of IL‐4 for CD4⁺ T‐cell differentiation into Th2. ⁸⁸ , ⁸⁹ , ⁹⁰ , ⁹¹ In contrast, other studies have found an inverse function of IL‐33 in the heart diseases. For example, pericarditis induced by IL‐33 in naïve and coxsackievirus B3‐infected mice results in increasing the proportion of eosinophils and ventricular dilation. ⁹² Also, it is found that the expression of IL‐33, promoting the transformation of ILC2 in heart (Figure 1), is mainly derived from CD29⁺Sca‐1⁺ cardiac fibroblasts both in experimental autoimmune myocarditis and MI models. ⁵⁹ The inflammation of IL‐33‐induced pericarditis in Rag2^−/−IL‐2Rγ^−/− mice is relieved for the deficiency of lymphocytes including ILC2s; however, adoptive transfer of ILC2s into Rag2^−/−IL‐2Rγ^−/− mice restores the susceptibility of eosinophil infiltration; up‐regulated expression of eotaxin‐1 by cardiac fibroblasts dependent on IL‐5 secreted by ILC2s, and as a result, it promotes eosinophils to traffic into the heart directly. ⁹³ Moreover, ILC2s can be stimulated to release IL‐5 through vasoactive intestinal peptide receptor type 2, which indicated that central circadian rhythms also involve in mediating basal eosinophilopoiesis and tissue eosinophil infiltration and accumulation. ⁹⁴ Recently, many data have demonstrated that neuropeptides produced by neuronal, including positive regulators, such as neuromedin U and negative regulators, such as calca‐encoding calcitonin gene‐related peptide and β2‐adrenergic receptor, serve as mediators in ILC2 proliferation and effector cytokine production. ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ For example, ILC2 expresses neuromedin U receptor 1 involving in promoting ILC2‐mediated type 2 inflammation by increasing ILC2 frequency, ⁹⁶ , ⁹⁷ , ⁹⁸ whereas neuropeptide calca‐encoding calcitonin gene‐related peptide co‐operates with neuromedin U and IL‐33 increasing IL‐5 expression and constraining ILC2s accumulation and IL‐13 production in lung inflammation. ⁹⁹ , ¹⁰⁰

ILC3 mainly expresses IL‐22 and IL‐17. IL‐17 has a great influence on the injury after MI, especially on ventricular remodelling. It has been indicated that IL‐23/IL‐17 axis obviously up‐regulated in myocardium following post‐MI. ¹⁰² , ¹⁰³ IL‐17 as a contributor in promoting the development of cardiac diseases to dilated cardiomyopathy through their effects on cardiac fibroblasts. ¹⁰⁴ , ¹⁰⁵ IL‐17 results in cardiomyocyte apoptosis and participates in post‐MI ventricular remodelling through MAPK‐p53‐Bax signalling pathway. ¹⁰⁶ Other data show that the size of MI decreases and the cardiac function improves in IL‐17‐deficient MI model. ¹⁰⁷ The status of IL‐22 in cardiac diseases is controversial. Some data show that IL‐22 has a protective effect; for example, IL‐22 inhibits myocardial fibrosis in viral myocarditis and alleviates the pathological changes of rat heart tissue by reducing the stimulation of IL‐1. ¹⁰⁸ , ¹⁰⁹ However, the deficiency of IL‐17 or IL‐22 will not protect the heart from the inflammation of viral myocarditis. ¹¹⁰ Moreover, the expression of ILC3‐derived IL‐22 is decreased without neurotrophic factors RET which as a mediator influence ILC3s responsiveness to the external environment and signals. ¹¹¹ There are no data addressing the role of ILC3s in heart disease, but ILC1s and ILC3s exist in myocarditis and MI ⁵⁹ ; the number is less than ILC2s, so the value of ILC1s and ILC3s still needs to be studied.

HELPER ILCs IN VASCULAR DISEASE

A lot of studies have shown that plaque burden decreased in the atherosclerosis mice model lacking T‐bet, IFN‐γ and IL‐12, indicating the relationship between Th1 and atherosclerosis. ¹¹² , ¹¹³ , ¹¹⁴ As a mirror cell of Th1, ILC1s sorted from the spleen of ApoE^−/− TLR4^+/+ mice are transferred into ApoE^−/− Rag1^−/− mice with anti‐NK1.1 mAbs for depleting ILC1 cells and aggravate atherosclerosis, whereas ILC1s from ApoE^−/− TLR4^−/− mice block the progression of atherosclerosis, and the size of atherosclerotic plaque in ApoE^−/− Rag1^−/− mice with the knockdown of ILC1s is smaller than that in NKs knockdown mice. ¹¹⁵ ILC1s in atherosclerosis express CD127, IFN‐γ, T‐bet, IL‐6 and IL‐1β, but lack c‐Kit, CD34, GATA‐3 and RORγt, distinct with NK cells. ¹¹⁶ IL‐12 plus IL‐18 could stimulate ILC1s from the spleen to secret IFN‐γ in vitro, whereas IL‐23 and IL‐1β cannot. The increase of IFN‐γ produced by ILC1 in ApoE^−/− mice induced by oxLDL is related to the decrease of Bach2 expression. ILC1s respond to atherosclerosis danger signals may convey by the signalling pathway of TLR4/BACH2, which has significant effects on atherosclerosis in the early stage. ¹¹⁵

ILC2s are mainly distributed in lung and AT and can spontaneously secrete IL‐5. Similarly, the aortic CD90⁺ ST2⁺ Sca‐1⁺ CD117⁺ ILC2s can also produce IL‐5 to promote the proliferation of IgM‐secreting B cells through the regulation of transcription factor Id3. ¹¹⁷ Th2 has a protective effect as its production of IL‐4 and IL‐5 decelerate disease progression; however, IL‐4 produced by ILC2s benefits Th2 differentiation. ⁹¹ , ¹¹⁸ , ¹¹⁹ ILC2s have been authenticated in the atherosclerotic aorta of Ldlr^−/−Rag1^−/− mice, and CD25⁺ ILCs expanded by IL‐2/anti‐IL‐2 complexes can ameliorate atherosclerosis. Notably, the administration of IL‐2/anti‐IL‐2 also causes early signs of fibrosis in liver; however, it remains unclear whether the impact on lipid and cholesterol levels is due to the physiological correlation of ILC2s or just due to the pathological impact of chronic ILC2s activation on liver injury and scar formation. ⁷⁴ IL‐33 and IL‐25 derived from epithelial cells are key activators of ILC2s and have an important role in injury or inflammation. IL‐33 decreases atherosclerosis in mice, while injecting the soluble ST2 promotes atherosclerosis progression. ¹¹⁸ Similarly, IL‐25 administration reduced atherosclerosis with increasing the number of ILC2s and their cytokines levels in serum (Figure 2). ¹¹⁹ Moreover, the lesional collagen content is increased in mice with IL‐13 treatment, whereas reduces monocyte recruitment; and lack of IL‐13 results in the aggravation of atherosclerosis. ¹²⁰ IL‐4 from activated ILC2s functionally antagonizes the production of allergen‐specific Treg, while atherosclerosis is exacerbated significantly for Treg depletion. ¹²¹ , ¹²² Another study demonstrates that thymic stromal lymphopoietin plays a protective role in atherosclerosis that is mainly associated with reducing the macrophage infiltration and increasing lesional Treg. ¹²³ , ¹²⁴

Figure 2.

The role of the helper ILCs in vascular disease. In atherosclerotic plaque, ILC1s express transcription factor T‐bet induced by IL‐12 plus IL‐18 to produce a high level of IFN‐γ and aggravate atherosclerosis. CD25⁺ ILC2s can be induced to produce cytokines IL‐4, IL‐5, IL‐13 and promote the increase of M2 and Th2 cells to change lipid metabolism to reduce atherosclerosis. Circulating ILCs in blood vessels enter atherosclerotic plaques and participate in the formation of early atherosclerotic plaques. Macrophage phagocytosis of oxLDL forms foam cells, releasing IL‐1β, and promotes ILC3s to release IL‐17.

In the past decade, there are almost no published data of ILC3s in human or mice atherosclerosis. Mucosal tissue and skin are the common region of T cells and ILC3s secreting IL‐22 and IL‐17 to maintain barrier homeostasis. The treatment of ApoE^−/−IL17A^−/− mice with IL‐17 aggravates the pathological changes, involving in the decrease of the smooth muscle cells and collagen, and plaque instability. ¹⁰⁷ , ¹²⁵ Conversely, other studies have indicate that IL‐17 reduces atherosclerotic lesion formation on atherosclerosis in the mice of IL‐17 or IL‐17RA gene knockout. ¹²⁶ Higher expression of RORγt and T‐bet was observed in ApoE^−/− mouse atherosclerotic plaques, which results in higher levels of IFN‐γ and IL‐17. Furthermore, IL‐17 and IFN‐γ double production cells can be seen in the vascular wall, which is related to the size of the lesion. Although the authors only detect Th1 and Th17, ILC1s and ILC3s may also play critical roles in the pathogenesis of atherosclerosis. ¹⁰⁷

Anti‐neutrophil cytoplasm antibody‐associated vasculitis is a severe multi‐system autoimmune diseases affecting the microvasculature, including granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA), which is classified according to the presence of affected small blood vessels and granuloma or asthma. ¹²⁷ Despite the strong Th2 preponderance of EGPA, ILC2 has been proved to exist in the eosinophilic inflammatory site of humans. ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ Recent advances suggest that the increase of peripheral ILC2s accompaning with the higher IL‐33 in serum is related to disease activity in EGPA and the presence of active vasculitis shows the increase of serum IL‐33 concentration. ¹³² Other studies have shown that the total ILCs are decreased significantly containing the frequencies of ILC1s, while both ILC2s and ILC3s decrease during acute phase in granulomatosis with polyangiitis and microscopic polyangiitis in contrast with healthy controls. ¹³³ However, these studies do not fully explain the reason for ILCs changes in each subgroup, and the specific mechanism needs further study.

CONCLUSIONS AND FUTURE DIRECTIONS

ILCs are one of the important cell subset in maintaining homeostasis and involving in innate immune response. Recently, it has been proved that most ILC subsets, as the first line against external infection, settle in specific organs, but the crosstalk between ILCs and tissues is still not clear. No comprehensive studies are addressing ILCs properties in cardiovascular system, and most of the reported data were obtained from mouse models or descriptive results of a small number of human patients. Many studies on the role of ILCs in diseases are carried out in the context of the lack of T and B cells, which leads us to neglect the interaction between the adaptive immune and ILCs. It is worth noting that knockdown of ILCs in atherosclerosis model does not alleviate the lesions, while with drugs that can stimulate the expansion of ILC2 in vivo, the lesions are relieved. In addition, ILCs in the adjacent tissues may release some corresponding molecules to stimulate the corresponding inflammatory cells to act on the cardiovascular system. Future work needs to address the different subsets of ILCs in the inflammatory environment, which would be helpful to give a novel perspective of ILCs in CVD. The efforts will help to design preventive strategies for innate and adaptive immune responses in CVD.

CONFLICTS OF INTEREST

None.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.