*Contributed equally
Autoimmune diseases (AIDs) are characterized by dysfunction and tissue destruction, and recent studies have shown that interleukin (IL)-37 expression is dysregulated in AIDs. Among cytokines of the IL-1 family, most are pro-inflammatory agents, and as an anti-inflammatory cytokine, IL-37 may have the potential to alleviate excessive inflammation and can be used as a ligand or transcription factor that is involved in regulating innate and adaptive immunity. IL-37 plays important roles in the development of AIDs. This review summarizes the biological characteristics and functions of IL-37 and discusses the potential of IL-37 as a therapeutic target for effective cytokine therapy and as a biomarker in AIDs.
The interleukin (IL)-1 family of cytokines plays a major role in regulating the expression of genes related to inflammation in autoimmune diseases (AIDs) (
IL-37, commonly known as IL-1F7, is a member of the IL-1 family of cytokines identified ten years ago (
An additional structural feature of IL-37 is its existence as a dimer (homodimer). It has been shown that this structure is found mostly in the IL-37b subtype. A symmetrical head-to-head IL-37b homodimer interface is created by the β3-β4 loops and β-trefoil sheet (β2-β3-β11) of each subunit. This dimer is a negative regulator of IL-37 activity, and the formation of such dimers weakens the anti-inflammatory effect of extracellular IL-37(
IL-37 is widely expressed in multiple human tissues and organs, including the skin, heart, kidney, gut, lymph node, thymus, bone marrow, lung, testis, placenta, and uterus (
IL-37 is expressed at low levels under physiological conditions, but can be upregulated in response to inflammatory stimuli and pro-cytokines. For example, IL-37 is mainly produced by macrophages in response to Toll-like receptor (TLR) activation (
In different cells, such as peripheral blood mononuclear cells (PBMCs), RAW-IL-37 cells, dendritic cells (DCs), epithelial cells, endothelial cells, and T cells, IL-37 can be upregulated by various pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-1β, transforming growth factor-β1 (TGF-β1; low concentrations), IL-4, and IL-6(
IL-37 primarily reduces innate and acquired immune responses through intracellular and extracellular inhibition by reducing the secretion of pro-inflammatory chemokines (
The
IL-37 binds to Smad3, dimers of which eventually enter the nucleus. Complexes formed in the cytoplasm by mature IL-37 and phosphorylated activated Smad3 translocate into the nucleus, where they are involved in regulating transcriptional activity (
The primary function of IL-37, an anti-inflammatory cytokine, is the secretion of proteins to the exterior of cells, which act as ligands for a functional receptor structure on the target cell membrane. The β-barrel structure of IL-37b binds to the α chain of the IL-18 receptor (IL-18R) and reduces the production of inflammatory mediators (
Formation of triplex complexes is critical for the anti-inflammatory effects of IL-37 and can coordinate innate immune responses by inducing the activation of myeloid differentiation factor 88 (MyD88) (
IL-37 forms a complex with IL-18Rα and IL-1R8 (previously TIR8 or SIGIRR), which can markedly reduce the anti-inflammatory activity of IL-37, indicating that the formation of the IL-37 receptor complex is required for IL-37 to fulfill its biological activities (
Currently, there is no evidence linking IL-37 to autophagy. However, the potential role of IL-37 in autophagy is currently unknown, although certain studies have revealed a potential link between them. IL-37 enhances autophagy and induces metabolic reprogramming by reducing mTOR expression and increasing the AMPK levels, resulting in changes in the cellular redox state, or by increasing oxidative phosphorylation (
Accumulating evidence shows that the expression of IL-37 is closely related to various AIDs such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (pSS), ankylosing spondylitis/spondyloarthritis (AS/SpA), vasculitis, gout, and osteoarthritis (OA) (
Inflammatory arthritis (IA) is a prevalent joint inflammatory illness, in addition to RA, OA and spondyloarthritis (
RA is a chronic inflammatory disease that can cause irreversible joint damage and physical disability. It can involve the skin, eyes, lungs, heart, and blood vessels (
As previously reported, the amount of IL-37 in normal human plasma and bodily fluids is exceedingly low, but is markedly increased in the synovial fluid, serum, and PBMCs of patients with RA (
The proportion of CD3+ CD26+ T cells is associated with disease activity, implying that IL-37 levels are positively correlated with activated T lymphocytes (
A previous study indicated that angiogenesis is a crucial mechanism for the proliferation of synovial tissue and the formation of invasive pannus in the early onset of RA (
In an
The role of IL-37 single nucleotide polymorphisms (SNPs) in RA is debatable. A Chinese RA population study revealed that IL-37 rs3811047 is positively associated with disease activity, indicating that the prognosis of RA patients with various IL-37 genotypes varies (
Collectively, IL-37 may be presented as a novel biomarker for predicting and monitoring disease severity/therapeutic targets in RA by reducing inflammation.
AS/SPA is a chronic inflammatory illness that affects the sacroiliac joints, spine bony processes, paraspinal soft tissues, and peripheral joints, with extra-articular symptoms occurring in certain cases (
The level of IL-37 in the serum and PBMCs of patients with AS was revealed to be higher than that in healthy controls (HCs), and was was associated with ESR, CRP, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS), and bone density. It was found that IL-37 can inhibit the expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-17, and IL-23) in PBMCs of patients with AS, indicating a potential anti-inflammatory role of IL-37 in AS (
The A/G frequency of
In conclusion, the aforementioned studies suggested that IL-37 plays significant roles in the development of AS/SPA. IL-37 may be used as a predictive biomarker for AS, as well as to assess the degree of inflammation and bone loss.
Gout is caused by the precipitation of monosodium urate (MSU) crystals within joints and soft tissues that can progress to acute or chronic arthritis (
Several studies have shown that IL-37 expression is increased in PBMCs of patients with gout (
Different doses of MSU have been shown to elicit dose-dependent overexpression of IL-37 protein and mRNA in PMBCs
The mRNA level of pro-
Therefore, rhIL-37 has both preventive and therapeutic effects on gout, and the suppressive effect of IL-37-mediated inflammation may partially depend on the activation of MERTK (
Using a molecular inversion probe sequencing technique, four unusual IL-37 variations were detected in 675 individuals with gout. It is possible that carriers of p.(N182S) (rs752113534) are at a higher risk of developing gout and undergo early onset of disease (
These studies revealed that IL-37 may be a potentially valuable treatment option for patients with chronic gout, especially those with tophi and kidney damage.
OA is one of the most frequent degenerative joint disorders that affects people globally (
Ding
Another study, using immunohistochemical assays revealed that the IL-37 protein was dysregulated in human OA chondrocytes, which could inhibit osteoclast differentiation directly (
These studies indicated that IL-37 may prevent cartilage deterioration in individuals with OA. The presence of IL-37 may be a useful marker to distinguish EIOA from PGOA. It is anticipated that rhIL-37 will serve as a new therapeutic option for individuals with specific types of OA.
SLE is an autoimmune disease involving the activation of autoreactive B cells and the dysregulation of numerous other types of immune cells, including CD4+ T cells, DCs, macrophages, and neutrophils. SLE is highly heterogeneous in its various presentations and is characterized by multiple organ damage (
Treatment with prednisone (1 mg/kg/day for 14 days) substantially decreased plasma IL-37 expression in SLE patients (
IL-37 may play an important role in the inhibition of SLE pathogenesis. Thus, it is expected to serve as a diagnostic and prognostic tool. Further studies are required to identify the mechanisms underlying IL-37 regulation during the mediation of immune reactions in SLE.
pSS is an autoimmune disease characterized by focal lymphocytic infiltration of exocrine glands such as the salivary and lacrimal glands. Inflammatory response immune aberrations underlying pSS are mediated by B and mast cells (MCs) (
BD is a multisystem disorder characterized by primary vasculitis of unknown etiology. Vasculitis and thrombotic events are the most common causes of death (
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TSLP is upregulated during the acute phase of BD, and is associated with skin lesions. It has been shown that rhIL-37 may reduce the levels of TSLP
IL-37 alters immune dysregulation in pSS and BD. It can be considered as a new biomarker with potential therapeutic application.
ITP is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100x109/l), in the absence of other causes and disorders that may be associated with thrombocytopenia (
Thus, IL-37 may be involved in ITP pathogenesis. Current studies suggest that IL-37 levels are elevated in the PBMCs or serum of patients with ITP (
MS is one of the most prevalent neurological dysfunctions and is an autoimmune disease that affects the central nervous system (CNS), often leading to severe physical or cognitive loss and neurological problems in patients (
Studies have shown that IL-37 is aberrantly expressed in MS patients (
The serum levels of IL-37 and sVEGFR2 and the circulatory number of VEGFR2-expressing cells were higher in patients with MS than in HCs (
AIDs refer to the set of ailments that arise when the immune system of the body launches an assault on self-tissues. This involves the production of aberrant antibodies. IL-37, a member of the IL-1 family, can decrease both congenital inflammation and acquired immunological responses. Although the mechanism underlying IL-37 function is not entirely understood, it is known to be associated with the development of AIDs. IL-37 plays a crucial role in protecting tissues from damage in AIDs by suppressing excessive inflammatory responses. A transgenic IL-37tg mouse model showed that IL-37 exerts considerable anti-inflammatory effects (
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HZ, KZ and ZY designed the study and wrote the manuscript. HZ and KZ performed literature review. KZ and ZY conceived the review and edited the manuscript. All authors have read and approved the final version of the manuscript. Data authentication is not applicable.
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The authors declare that they have no competing interests.
Role of IL-37 regulation of immunity. IL-37 has significant anti-inflammatory, anticancer, immuno-suppressive, and metabolic regulatory effects. IL-37 binds to IL-18Ra or IL-18BP, which can enhance inhibition of IL-18 and reduce inflammation. The homodimer of IL-37 is a negative regulator of extracellular anti-inflammatory activity. IL-37 is translocated to the nucleus after being processed by caspase-1, and precursor IL-37 is processed into mature IL-37. Complexes formed by mature IL-37 and phosphorylated activated Smad3 in the cytoplasm undergo nuclear translocation into the nucleus, where they play a role in regulating transcriptional activity. PTPNs are activated and numerous related inflammatory and immune pathways are inhibited, including ERK, MAPK, JNK, PI3K, NF-κB, and STAT3. IL-37 binds to its receptor IL-18Rα, recruiting the co-receptor IL-1R8 to form the IL-37/IL-18Rα/IL-1R8 complex at the plasma membrane induced by inhibiting MyD88-dependent signaling. IL-37 negatively regulates inflammatory responses in the innate and acquired immune system by downregulating IRAK, PTEN, ROS, TRAF6, NLRP3, mTOR, TSLP, MHC-II, and CD86. IL-37 acts as an anti-inflammatory cytokine by decreasing the production of pro-inflammatory cytokines and chemokines. IL-37 enhances autophagy and induces metabolic reprogramming by reducing the expression of mTOR and increasing the AMPK levels. However, molecular mechanisms of IL-37-mediated autophagy remain unknown. IL-18Ra, α-subunit of IL-18 receptor; IL-18BP, IL-18 binding protein; PTPNs, protein tyrosine phosphatases; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; PI3K, phosphatidylinositol-3-kinase; NF-κB, nuclear factor-κB; STAT, signal transduction and activator of transcription; MyD88, myeloid differentiation factor 88; IRAK, interleukin-1 receptor-associated kinase 1; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; TRAF6, TNF receptor-associated factor 6; NLRP3, NOD-like receptor family pyrin domain containing 3; mTOR, mammalian target of rapamycin; TSLP, thymic stromal lymphopoietin; AMPK, AMP-dependent protein kinase.
IL-37 in autoimmune disease.
Disease | Role of IL-37 | (Refs.) |
---|---|---|
RA | Associated with proinflammatory factors, TLR4 | ( |
Associated with disease activity | ( |
|
Associated with activated T cell function | ( |
|
Associated with bone loss | ( |
|
Inhibits RAFLS proliferation and migration; induces RAFLS apoptosis by inhibiting the STAT3 pathway | ( |
|
AS/SPA | Associated with bone density | ( |
Associated with disease activity | ( |
|
GOUT | Associated with proinflammatory factors | ( |
Associated with disease activity | ( |
|
Associated with tophi forming, kidney deterioration | ( |
|
rhIL-37 suppressed MSU-induced innate immune responses by enhancing expression of Smad3 and IL-1R8 to trigger multiple intracellular switches to inhibit NLRP3 and the activation of SOCS3 | ( |
|
Reduces the transcription of pyrophosphate-related proteins and release of inflammatory cytokines by enhancing phagocytosis of MSU, protects mitochondrial function, and mediates metabolic reprogramming in THP-1 cells treated by MSU, which depended on the mediation of GSK-3 β | ( |
|
OA | Associated with VAS | ( |
Affects M1/M2-like macrophage polarization | ( |
|
Associated with proinflammatory factors | ( |
|
rhIL-37 may regulate the key downstream target MMP-3 | ( |
|
SLE | Associated with disease activity (SLEDAI) | ( |
Associated with kidney damage and skin lesion. | ( |
|
Associated with Asian race | ( |
|
Associated with proinflammatory factors | ( |
|
Negatively correlated with C3/C4, and antibodies | ( |
|
Associated with C3 | ( |
|
PSS | Associated with RF, antibodies, proinflammatory factors | ( |
BD | Negatively correlated with inflammatory response | ( |
rhIL-37 may reduce the levels of TSLP |
( |
|
ITP | Positive correlate with the platelet count | ( |
Positive correlate with proinflammatory factors | ( |
|
MS | Act as a part of a feed-back loop to control underlying inflammation | ( |
Positive correlate with disease activity | ( |
|
Regulate autophagy, apoptosis | ( |
RA, rheumatoid Arthritis; TLR, Toll-like receptor; RAFLS, fibroblast like synoviocytes; AS, ankylosing spondylitis; SPA, spondyloarthropathy; MSU, monosodium urate; NLRP3, NOD-like receptor family pyrin domain containing 3; SOCS3, suppressor of cytokine signaling 3; OA, osteoarthritis; VAS, visual analogue scale; MMP3, matrix metalloproteinase-3; SLEDAI, systemic Lupus Erythematosus Disease Activity Index; C, complement; PSS, primary Sjögren's syndrome; BD, Behcet's disease; RF, rheumatoid factor; TSLP, thymic stromal lymphopoietin; ITP, immune thrombocytopenic purpura; MS, multiple sclerosis.