Academic Editors: Giuseppe Biondi-Zoccai, Mariangela Peruzzi and Antonio Abbate
Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) directly interact
with intracellular interleukin receptor associated kinase (IRAK) family members
to initialize innate immune and inflammatory responses following activation by
pathogen-associated or host-derived elements. Although four IRAK family members
[IRAK1, 2, 3 (i.e., IRAK-M), and 4] are involved in TLR and IL-1R
signaling pathways, IL-1R
Cardiovascular disease (CVD) is the leading cause of death worldwide [1]. The mechanisms underlying CVD are extremely complex, involving interactions among multiple local and global factors [2]. Over the past several decades, evidence has demonstrated that both the innate and adaptive immune systems play essential roles in maintaining homeostasis and in the development of CVD [3]. For example, atherosclerosis, originally only referred to as an arterial disease, is now also classified as a chronic inflammatory disease [4]. Similarly, myocardial infarction (MI) was also found to be highly associated with immune responses [5]. Therefore, prevention, reduction, and inhibition of inflammation-induced damage might be an effective approach to prevent and treat CVD in addition to classical medication and surgery.
Traditionally, the immune system can be divided into two categories, the innate
immune system and the adaptive immune system [6, 7]. The innate immune system is
the body’s first defense for both infectious and noninfectious pathogens, where
innate immune cells, such as neutrophils, monocytes, macrophages, and dendritic
cells, are activated by pathogen-bound toll-like receptor (TLR) signaling [8].
Interestingly, endothelial cells (ECs), which line the inside of the heart and
all blood vessels and directly interact with the bloodstream, can also present
exogenous antigens to either CD4
As in other tissues and organs in the body, both the innate and adaptive immune systems also protect the cardiovascular system immediately following infection (e.g., virus and bacteria) or non-infection (e.g., MI and heart arrest) injury [12]. The innate immune system is an early responder to cardiac injury and involves activation and recruitment of pro-inflammatory innate immune cells to the damaged site; the intermediate and late stages comprise activation and recruitment of anti-inflammatory immune cells for tissue remodeling and repair [5]. However, both over- and under-reaction (e.g., cytokine storm-induced EC damage in COVID-19 [13] and human cytomegalovirus-induced cardiac dysfunction [14]) of either immune system can lead to CVD [5].
Two molecular patterns are now known to individually or simultaneously activate cardiac resident innate immune cells via pattern recognition receptors (PRRs), such as TLRs and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) on stressed ECs [15]. These molecular patterns include (a) Pathogen associated molecular patterns (PAMPs), such as circulating endotoxin; and (b) Damage associated molecular patterns (DAMPs), such as cellular debris from injured cardiomyocytes. Among these patterns, the interleukin receptor-associated kinase (IRAK) family plays a crucial role in both TLR- and interleukin-1 receptor (IL-1R)-based activation and modulation of the innate immune response following cardiovascular injury [16].
Well-documented evidence demonstrates that IRAK1 is one of the central kinases involved in the development of various diseases, such as cancer, metabolic disorders (e.g., diabetes), infection (e.g., sepsis), and non-infectious immune diseases (e.g., systemic lupus erythematous) [17]. Because the cardiovascular system (heart and vessels) is known to be modulated by inflammatory cytokines, immune cells, and metabolites [18, 19], it is not surprising that IRAK1, as a key mediator of the innate immune response, plays an essential role in the pathogenesis of CVD. Although new evidence shows that other IRAK members (e.g., IRAK3 [16]) are also involved in the development of CVD, we will focus on the overall roles of IRAK1 in modulating inflammatory responses to MI and vascular injury in this review, due to the very limited publications on other IRAK members regarding their association with CVD. Increasing evidence indicates that IRAK1 not only promotes CVD progression but also has the potential to become a new therapeutic target for drug discovery and future treatment of CVD patients.
The IRAK family is made up of 4 members—IRAK1, IRAK2, IRAK3 (also known as IRAK-M), and IRAK4 [20]. All members share similar functional and structural domains, including a N-terminal death domain (DD), a proline/serine/threonine (ProST) domain, and a kinase or pseudokinease domain (KD or PKD) [21]. Except for IRAK4, the rest of the IRAK members contain an additional C-terminal domain (CD), which is required for activation of tumor necrosis factor receptor-associated factor 6 (TRAF6) [21]. DD plays an important role in TLR and IL-1R signaling by interacting with the myeloid differentiation primary response protein 88 (MyD88). Whereas the ProST domain, which contains 2 peptide sequences rich in proline (P), glutamic acid (E), serine (S), and threonine (T) (the so-called PEST sequence), is responsible for hyperphosphorylation and degradation of IRAK1 [22, 23].
IRAKs were first functionally described as key mediators in coordinating multiple IL-1 signaling pathways and in facilitating production of pro-inflammatory cytokines, but later, IRAKs were also found to be implicated in signal transduction through TLRs [21]. Each IRAK family member exerts a different role in modulating TLRs-/IL-1R-associated downstream responses. Following activation of TLRs-/IL-1R, MyD88 and IRAK proteins are recruited to form the receptor complex [22, 23], in which IRAK4, as an upstream kinase, activates IRAK1 and IRAK2 through phosphorylation. Phosphorylated IRAK1 and 2 can cause some common or different functional effects. In the early phase, both IRAK1 and IRAK2 have the same function, which is associated with an acute inflammatory response; while in the late phase, IRAK2 is believed to be involved in chronic inflammatory responses [24].
Activation of IRAKs (1, 2, and 4) by TLRs/IL-1R leads to stimulation of various
downstream signaling pathways, especially the nuclear factor kappa B
(NF-
IRAK1-mediated signaling pathways in cardiovascular and immune
cells. Injured CMs, ECs, and VSMCs release DAMPs, which then bind to TLRs/IL-1R
on immune cells and cardiovascular cells (CMs, ECs, and VSMCs) and activate
downstream inflammatory pathways including: (a) IRAK1
IRAK1, the first-discovered and most-studied member of the IRAK family, is known
to play an important role in mediating IL-1-associated immune and inflammatory
responses by activating NF-
IRAK1 comprises 3 splice variants (1b, 1c, and 1s) as well as a full-length form
and each variant has its unique biological function. For example, IRAK1b remains
active and extremely stable after being activated by IL-1 signaling, thus,
leading to the sustainable activity of NF-
The involvement of TIR domain-associated IRAK1
NLRs are the only cytoplasmic receptors that recognize pathogen-derived
intracellular invaders (i.e., PAMPs) and non-infectious danger signals
(i.e., DAMPs from injured cardiac cells [40]) among the four members of
PRR [TLRs, NLRs, C-type lectin receptors (CLRs), and RIG-1 like receptors (RLR)]
[41, 42] (also see Fig. 1). Activation of NLRs by TIR domain signaling promotes
the formation of inflammasomes, which then activate Caspase-1/4/5/11, leading to
the production of the pro-inflammatory cytokines IL-1
The first known role of IRAK1 is the mediation of signal transduction from TLRs
to inflammatory cytokines via the NF-
TLRs can be recognized and activated by two types of ligands, PAMPs and DAMPs as mentioned above. PAMPs refer to infectious pathogens, such as PS, phospholipids, extracellular matrix, peptide, and nucleic acids released from bacteria; while DAMPs denote non-infectious endogenous molecules, such as heat shock proteins 60/70/72 (HSP60, 70, and 72) and high mobility group box 1 (HMGB1) protein released from, for example, injured cardiomyocytes [3, 46]. Studies indicate that all TLRs contain an extracellular domain with leucine-rich repeat (LRR) motifs specific for recognizing TLR ligands, whereas all IL-1Rs contain three immunoglobulin-like domains (Ig-like domains) specific for recognizing IL-1 ligands [24]. Since TLRs and IL-1Rs share the same homologous TIR domain, IRAK1 could participate in both TLR- and IL-1R-mediated signaling, suggesting its biological importance [24].
Activation of TLRs/IL-1R causes a series of intracellular reactions in the
downstream signaling cascades, including recruitment of the TIR domain adaptors
such as MyD88 [47], formation of the IRAK1/4 and MyD88 complexes, IRAK1
phosphorylation by IRAK4, detachment of hyper-phosphorylated IRAK1 [17],
activation of TRAF6 [48]/transforming growth factor-
Atherosclerosis (often denoted as arteriosclerosis), which is characterized by lipid-laden foam cell accumulation in the arterial wall, is recognized as a chronic inflammatory disease [51]. As stated above, activation of IRAK1 enhances production of IL-10 [37] and patients with atherosclerosis often have an elevated level of IL-10, implying that the IRAK1-mediated innate immune response may play an important role in the development of atherosclerosis [37]. Numerous in vitro and in vivo studies listed below support these findings.
By genotyping 4 loci on the IRAK1 gene on the X chromosome of 996 Caucasian patients with Type 2 diabetes (467 men and 529 women), the Diabetes Heart Study identified two major haplotypes, CTTT (82%) and TCCG (13%), in the IRAK1 gene. The TCCG haplotype is significantly correlated with an enhanced blood level of C-reactive protein (CRP, an acute inflammation marker) in women but not in men [52]. Since blood concentration of CRP has been used to assess the risk of coronary artery disease and predict MI and stroke [53], the presence or overexpression of the TCCG haplotype in the IRAK1 gene may promote pathogenesis of CVDs [52].
On the other hand, the ATP-binding cassette subfamily A member 1 (ABCA1), a
crucial mediator of lipid efflux in the cell membrane, can be downregulated by
IRAK1 through TLR4 signaling pathway following treatment of oxidized low-density
lipoprotein (oxLDL) [54], suggesting IRAK1’s potential role in atherosclerotic
development. This hypothesis is supported by a similar study, in which IRAK1 was
found to increase lipid binding, uptake, and cholesterol efflux in foam cells
[55] (also see Fig. 2). However, inhibition of IRAK1 (by an IRAK1 antagonist,
such as IRAK1/4 inhibitor or its siRNA) significantly attenuated expression of
cluster differentiation 36 (CD36) [55]. It is known that CD36 is a crucial
macrophage scavenger receptor that is responsible for cellular cholesterol
accumulation, oxLDL internalization, and foam cell formation [55]. Downregulation
of CD36 may lead to beneficial effects in preventing or weakening the development
of atherosclerosis. Furthermore, inhibition of IRAK1 also increases expression of
ABCA1 and ATP-binding cassette subfamily G member 1 (ABCG1), which leads to
increased cholesterol efflux from macrophages [55]. This process is accompanied
by increased expression and activity of liver transcriptional X receptor alpha
(LXR
Working hypothesis of IRAK1-induced formation of atheromatous
foam cells in the vascular wall. It is known that foam cells are formed from
monocyte-derived M
IRAK1 also stimulates VSMC proliferation, which is a pivotal pathogenic process in the development of atherosclerosis [58]. Two signaling pathways are likely involved in IRAK1-associated VSMC proliferation: (a) the IL-1/IL-18 inflammatory pathway, in which activation of IRAK1 induces production of inflammatory cytokines such as IL-1 and IL-18 which, in turn, provokes VSMC proliferation during atherosclerosis progression [59]; and (b) the kinase pathway, in which IRAK1 facilitates VSMC proliferation and neointimal hyperplasia by activating protein kinase C (PKC) and extracellular signal regulated kinase (ERK) [60].
ECs, a major cell type involved in plaque formation in atherosclerosis, is also
found to be regulated by IRAK1 [61]. Alfaidi et al. [62] revealed that a
signaling adaptor, named non-catalytic region of tyrosine kinase 1 (Nck1), could
interact with IRAK1 under shear stress and trigger NF-
Growing evidence demonstrates that IRAK1 is also involved in the development of
cardiac diseases, such as MI and HF (Table 1, Ref. [65, 66, 67, 68, 69]). Thomas
et al. [65] reported that IRAK1 mediates LPS-induced myocardial
dysfunction of contractile through TIR domain signaling and knockout of the
Irak1 gene significantly reduces mortality of mice with HF. Because
atherosclerotic-induced MI and bacterial-induced cardiac septic shock share
common characteristics of myocardial dysfunction, pharmacological inhibition of
IRAK1 may reduce cardiac inflammation and provide beneficial effects for patients
with heart disease [3]. Similarly, studies using a mouse ischemia/reperfusion
model found that TLR4
Cardiac Disease | Animal Model | Experimental target | Major Findings and Conclusion |
Septic HF [65] | Irak1 |
Irak1 | |
MI (I/R) [66] | Tlr4 |
Tlr4 and Myd88 | |
Septic HF [67] | LPS-induced cardiac disorder in mice | miRNA-146a | |
MI (I/R) [68] | LAD ligation-induced MI in mice | miRNA-146a | |
MI (I) [69] | CME-induced MI in pig | miRNA-142 | |
Abbreviations: CM, cardiomyocytes; CME, coronary microembolization; EF, ejection
fraction; FADD, fas-associated death domain protein; HF, heart failure; HSP60,
heat shock protein 60; I/R, ischemia-reperfusion; IRAK1, interleukin-1
receptor-associated kinase 1; IL-1R, interleukin-1 receptor; LAD, left anterior
descending; LPS, lipopolysaccharides; MI, myocardial infarction; miRNA, microRNA;
MyD88, myeloid differentiation primary response protein 88; NF- |
Recent studies suggest that small non-coding RNAs [e.g., microRNA
(miRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and
Piwi-interacting RNA (piRNA)] are also involved in pathogenesis through
modulation of IRAK1 [71]. Among ~2000 miRNAs, miRNA-146a was
first identified as a negative regulator targeting IRAK1 and TRAF6 and reduced
the TLR-triggered innate immune response [72]. This finding was supported by a
gain-of-function study using the same model of mouse MI. In this study, increased
expression of miRNA-146a decreased cardiac infarct size (~50%)
and increased cardiac function, which was believed to be due to direct inhibition
of IRAK1 and TRAF6 by miRNA-146a [68]. Another study also found that miRNA-146a
diminishes sepsis-induced cardiomyocyte apoptosis and infiltration of
inflammatory monocyte cells by inhibiting the same molecule (i.e., IRAK1
and TRAF6) [67]. New studies found that IRAK1 can also be regulated by other
miRNA, such as miRNA-142-3p. Su et al. [69] discovered that there is
significant downregulation of miRNA-142-3p in porcine MI induced by coronary
micro-embolization. Either up-regulation of miRNA-142-3p or down-regulation of
IRAK1 appears to be able to reduce production of NF-
IRAK1 is the most studied IRAK member within the TLR and IL-1R signaling pathways, where it plays an essential role initializing the innate immune response to both infectious pathogen invasion and non-infectious injuries. Much of the collected data has indicated that IRAK1 is highly associated with the pathogenesis of CVD, especially in the development of atherosclerosis, MI, and HF. Overall, this review demonstrates that IRAK1 is not only activated by multiple signaling molecules (e.g., TLR/IL-1R ligands) but it can also be inhibited by pharmacological agents with beneficial results, suggesting its potential as a new therapeutic target (in addition to other known targets, such as IL-1 and NLRP3) for drug discovery and development for patients with CVD. However, the detailed mechanisms underlying IRAK1-promoted cardiovascular injury, remodeling, and regeneration remain largely unknown. For example, what is the specific role of IRAK1 in the innate immune cells in response to MI following I/R? Are there any differences between cardiomyocytes and immune cells in terms of the function of IRAK1? How can the protective efficacy of the commonly used pre-conditioning strategy be enhanced by modulating IRAK1-mediated signaling? Is IRAK1 a better therapeutic target than other components (e.g., MyD88, IRAK4) within the TLR pathway? A substantial amount of work remains to be conducted to answer these questions.
JQH—conceived the idea; YZ—conducted the literature search and wrote the manuscript; JQH—revised the manuscript. All authors contributed to editorial changes in the manuscript and read and approved the final manuscript.
Not applicable.
We thank Janet Webster of the Fralin Life Sciences Institute at Virginia Tech for kindly providing a review of the manuscript.
This work was supported by the NIH grant (1R15HL140528-01 for JQH), One-Health seed grant (PJ6SPVHJ for JQH) by the College of Veterinary Medicine at Virginia Tech and the Edward Via College of Osteopathic Medicine, Interdisciplinary Graduate Education Program of Regenerative Medicine (IGEP-RM for YJZ), and Internal Research Competition (IRC) Seed Grant (#178391 for JQH) by the College of Veterinary Medicine at Virginia Tech. The funders had no role in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.
The authors declare no conflict of interest.