IL-33 is effective in reversing Alzheimer-like symptoms in APP/PS1 mice
(from WIKI)
Interleukin 33 (IL33) is a protein that in humans is encoded by the IL33 gene.[1]
Interleukin 33 is a member of the IL-1 family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL33 is a ligand for IL33R (IL1RL1), an IL-1 family receptor that is highly expressed on Th2 cells, mast cells and group 2 innate lymphocytes.
IL-33 is expressed on a wide variety of cell types, including fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells.[3]
IL-33 is effective in reversing Alzheimer-like symptoms in APP/PS1 mice, by reversing the buildup and preventing the new formation of amyloid plaques.[4]
IL-33 protein injection in AD mouse models alleviates Alzheimer’s symptoms
While the mechanisms underlying the onset and progression of AD remain unclear, scientists from the Hong Kong University of Science and Technology (HKUST) recently conducted a study on the potential therapeutic role of interleukin-33 (IL-33) in AD, where they injected the protein into transgenic mouse models of AD. The injection of IL-33 rescues contextual memory deficits and reduces the deposition of β-amyloid peptide (Aβ) in the transgenic mouse model, suggesting that IL-33 can be developed as a new therapeutic intervention for AD.
The findings were published in the journal PNAS.
“There is no effective therapy for AD, in part because of our limited knowledge of its underlying pathophysiological mechanisms,” said Prof Nancy Ip, Dean of Science, Director of the State Key Laboratory of Molecular Neuroscience and The Morningside Professor of Life Science at HKUST, who directed the research effort. “Nonetheless, targeting the innate immune system has been considered a promising strategy for developing effective ther
apeutics for AD. The present study demonstrates that peripheral IL-33 injection in AD mouse models alleviates AD-like pathology by enhancing microglial phagocytosis and degradation of Aβ.”
“We believe that IL-33 is a critical factor in maintaining a healthy brain,” Prof Ip said. “Disturbances in this signal mechanism, owing to genetic disposition or environmental influence, may contribute to the onset of AD. The next step will be to translate the findings from the mouse study into clinical treatments for humans.”
The research was the result of a collaborative effort among scientists from HKUST, the University of Glasgow, and Zhejiang University.
Explore further: Breakthrough research reveals a new target for Alzheimer’s disease treatment
More information: Amy K. Y. Fu et al, IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline, Proceedings of the National Academy of Sciences (2016). DOI: 10.1073/pnas.1604032113
Journal reference: Proceedings of the National Academy of Sciences search and more info website
Provided by: Hong Kong University of Science and Technology
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Role of IL-33 in the inflammation of several disease
Interleukin (IL)-33 is a new member of the IL-1 superfamily of cytokines that is expressed by mainly stromal cells, such as epithelial and endothelial cells, and its expression is upregulated following pro-inflammatory stimulation. IL-33 can function both as a traditional cytokine and as a nuclear factor regulating gene transcription. It is thought to function as an ‘alarmin’ released following cell necrosis to alerting the immune system to tissue damage or stress. It mediates its biological effects via interaction with the receptors ST2 (IL-1RL1) and IL-1 receptor accessory protein (IL-1RAcP), both of which are widely expressed, particularly by innate immune cells and T helper 2 (Th2) cells. IL-33 strongly induces Th2 cytokine production from these cells and can promote the pathogenesis of Th2-related disease such as asthma, atopic dermatitis and anaphylaxis.
However, IL-33 has shown various protective effects in cardiovascular diseases such as atherosclerosis, obesity, type 2 diabetes and cardiac remodeling. Thus, the effects of IL-33 are either pro- or anti-inflammatory depending on the disease and the model. In this review the role of IL-33 in the inflammation of several disease pathologies will be discussed, with particular emphasis on recent advances.
Basic Biology of IL-33
Interleukin (IL)-33 (also known as IL-1F11) was originally identified as DVS27, a gene up-regulated in canine cerebral vasospasm [1], and as “nuclear factor from high endothelial venules” (NF-HEV) [2]. However, in 2005 analysis of computational structural databases revealed that this protein had close amino acid homology to IL-18, and a β-sheet trefoil fold structure characteristic of IL-1 family members [3]. IL-33 binds to a ST2L (also known as T1, IL-1RL1, DER4), which is a member of the Toll-like receptor (TLR)/IL1R superfamily. IL-33/ST2L then forms a complex with the ubiquitously expressed IL-1R accessory protein (IL-1RAcP) [4-6]. Signaling is induced through the cytoplasmic Toll-interleukin-1 receptor (TIR) domain of IL-1RAcP. This leads to recruitment of the adaptor protein MyD88 and activation of transcription factors such as NF-κB via TRAF6, IRAK-1/4 and MAP kinases and the production of inflammatory mediators (Figure (Figure1)1) [3]. The ST2 gene can also encode at least 2 other isoforms in addition to ST2L by alternative splicing, including a secreted soluble ST2 (sST2) form which can serve as a decoy receptor for IL-33 [7], and an ST2V variant form present mainly in the gut of humans [8].
Signaling through ST2L also appears to be negatively regulated by the molecule single Ig IL-1R-related molecule (SIGIRR) and IL-33 induced immune responses were enhanced in SIGIRR-/- mice [9].
IL-33 release and signaling via ST2L. IL-33 is predominantly expressed by stromal cells such as epithelial and endothelial cells. Damage to these cells can induce necrosis and release of full length IL-33 which can activate the heterodimeric ST2L/IL-1RAcP …
IL-33 appears to be a cytokine with dual function, acting both as a traditional cytokine through activation of the ST2L receptor complex and as an intracellular nuclear factor with transcriptional regulatory properties [10].
The amino terminus of the IL-33 molecule contains a nuclear localization signal and a homeodomain (helix-turn-helix-like motif) that can bind to heterochromatin in the nucleus and has similar structure to the Drosophila transcription factor engrailed [2,11].
In a similar manner to which a motif found in Kaposi sarcoma herpesvirus LANA (latency-associated nuclear antigen) attaches its viral genomes to mitotic chromosomes.
Nuclear IL-33 is thought to be involved in transcriptional repression by binding to the H2A-H2B acidic pocket of nucleosomes and regulating chromatin compaction by promoting nucleosome-nucleosome interactions [12].
However, the specific transcriptional targets or the biological effects of nuclear IL-33 are unclear at present.
Both IL-1β and IL-18 are synthesized as a biologically inactive precursors and activated by caspase-1 cleavage under pro-inflammatory conditions and it was initially thought that IL-33 underwent similar processing by caspase-1 [3].
Recent studies suggest that proteolytic processing is not required for IL-33 signaling via ST2L [13]. It has been suggested that a new splice variant of IL-33 exists, which lacks the putative caspase-1 cleavage site, and is biologically active inducing signaling via ST2L [14].
In fact, cleavage of IL-33 by caspases appears to mediate inactivation of IL-33 and its pro-inflammatory properties [13,15-17]. Currently, it is thought that full length biologically active IL-33 may be released during necrosis as a endogenous danger signal or ‘alarmin’, but during apoptosis IL-33 is cleaved by caspases leading to inactivation of its pro-inflammatory properties [18].
IL-33, an inducer of Th2 immune responses
Unlike the other IL-1 family members IL-33 primarily induces T helper 2 (Th2) immune responses in a number of immune cell types (reviewed in detail in [19]). ST2L was initially shown to be selectively expressed on Th2, but not Th1 [20,21] or regulatory (Treg) T cells [22].
Subsequent studies have shown that IL-33 can activate murine dendritic cells directly driving polarization of naïve T cells towards a Th2 phenotype [23], and it can act directly on Th2 cells to increase secretion of Th2 cytokines such as IL-5 and IL-13 [3,24].
Furthermore, IL-33 can also act as a chemo-attractant for Th2 cells [25]. IL-33 can activate B1 B cells in vivo, markedly enhancing production of IgM antibodies and IL-5 and IL-13 production from these cells [3,26,27].
IL-33 is also a potent activator of the innate immune system
IL-33 is also a potent activator of the innate immune system. Schmitz and co-workers demonstrated that injection of IL-33 into mice induces a profound eosinophilia [3], and has potent effects on this cell type, including induction of superoxide anion and IL-8 production, degranulation and cell survival [28].
Subsequently, it has been shown that IL-33 is also a potent activator of mast cells and basophils and can induce degranulation, maturation, promote survival and the production of several pro-inflammatory cytokines in these cells [29-32].
In neutrophils, IL-33 prevents the down-regulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 [33]. Macrophages constitutively express ST2L and IL-33 can amplify an IL-13-driven polarization of macrophages towards an alternatively activated or M2 phenotype, thus enhancing Th2 immune responses [34]. IL-33 can also enhance LPS-induced production of TNFα in these cells [35].
Host defense against pathogens
It is likely that the primary role of these IL-33 effects on the immune system in evolutionary terms was in host defense against pathogens. In fact, IL-33/ST2 have been shown to be highly expressed and protective several parasite infections in animal models in which Th2 cells are host protective, including Leishmania major [36,37], Toxoplasma gondii [38], Trichuris muris [39], and Nippostrongylus brasiliensis [40]. Furthermore, a recent discovery has highlighted a new population of cells named nuocytes which expand in response to IL-33 and represent the predominant early source of IL-13 during helminth infection with Nippostrongylus brasiliensis [41]. However, it is clear that the potent activatory effects of IL-33 on several immune cell types is likely to impact on various inflammatory diseases.
Role of the IL-33/ST2 pathway in inflammatory diseases
Asthma
Asthma is a chronic inflammatory disease classically characterized by airway hyper-responsiveness, allergic inflammation, elevated serum IgE levels, and increased Th2 cytokine production. Given that IL-33 is a strong inducer of Th2 immune responses its role in asthma has been extensively studied (reviewed in [42]). Initial gene expression studies in a range of tissues using human and mouse cDNA libraries revealed expression of IL-33 in lung tissue, and high expression in bronchial smooth muscle cells [3].
Expression of IL-33 was found in higher levels in endobronchial biopsies from human asthmatic subjects compared to controls.
The IL-33 expression was particularly evident in those with severe asthma and the expression was mainly located in bronchial epithelial cells.
Studies to investigate which cells were the main IL-33 responsive cells in lung demonstrated that both epithelial and endothelial cells, but not smooth muscle cells or fibroblasts were important .
Several animal model studies have highlighted a functionally important role for IL-33/ST2 in asthma and allergic airways inflammation.
In a murine ovalbumin-induced airway inflammation model, intranasal administration of IL-33 induces antigen-specific IL-5+ T cells and promotes allergic airway disease even in the absence of IL-4 [24].
Intranasal IL-33 also promotes airways hyper-responsiveness, goblet cell hyperplasia, eosinophilia, polarization of macrophages towards an M2 phenotype, and accumulation of lung IL-4, IL-5 and IL-13.
More recently, an IL-33 transgenic mouse was generated in which IL-33 expression was controlled under a CMV promoter and released as a cleaved 18 kDa protein in pulmonary tissue .
These mice developed massive airway inflammation with infiltration of eosinophils, hyperplasia of goblet cells and accumulation of pro-inflammatory cytokines in bronchoalveolar lavage fluid.
In contrast, intraperitoneal anti-IL-33 antibody treatment inhibited allergen-induced lung eosinophilic inflammation and mucus hypersecretion in a murine model.
Administration of blocking anti-ST2 antibodies or ST2-Ig fusion protein inhibited Th2 cytokine production in vivo, eosinophilic pulmonary inflammation and airways hyper-responsiveness.
At present, the role of IL-33/ST2 in studies using ST2-deficient mice is unclear as these mice are not protected in the ovalbumin-induced airway inflammation model but have attenuated inflammation in a short-term priming model of asthma.
Furthermore, there is also an exacerbation of disease in wild-type or Rag-1-/- mice that had undergone adoptive transfer of ST2-/- DO11.10 Th2 cells [24,51,52].
In order to clarify the role of IL-33/ST2 in lung inflammation, several groups have generated mice deficient in IL-33. Oboki and co-workers demonstrated that 2 sensitizations of IL-33-/- mice with ovalbumin emulsified in alum showed attenuated eosinophil and lymphocyte recruitment to the lung, airway hyper-responsiveness and inflammation [19].
A similar study by Louten and colleagues has also shown that endogenous IL-33 contributes to airway inflammation and peripheral antigen-specific responses in ovalbumin-induced acute allergic lung inflammation using IL-33-/- mice [53]. Collectively, the data suggest that IL-33 is involved in lung inflammation and supports the concept of ST2 as a therapeutic target in asthma.
Rheumatological diseases
Recent evidence suggests a role for IL-33/ST2 in several rheumatological diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA) and systemic lupus erythematosus (SLE). The first study to link IL-33 expression with arthritis utilized in situ hybridization to show that IL-33 mRNA expression in the RA synovium is primarily in endothelial cells [11]. Subsequently, IL-33 protein has been found in endothelial cells of synovial tissue and in cells morphologically consistent with synovial fibroblasts in a subset of RA, PsA and OA patients [54]. IL-33 is also expressed in cultured synovial fibroblasts from patients with RA and expression was markedly elevated in vitro by inflammatory cytokines [55,56]. Circulating IL-33 protein has also been detected in 94/223 RA patient serum samples by ELISA, but was completely absent in healthy controls or OA samples [57]. Furthermore, the level of serum IL-33 decreased after anti-TNF treatment and correlated with production of IgM and RA-related autoantibodies including Rheumatoid Factor and anti-citrullinated protein antibodies. Serum and synovial fluid levels of IL-33 have also been shown to decrease in patients who respond to anti-TNF treatment, while they did not change in non-responders [58]. Similarly, Talabot-Ayer and co-workers show that serum and synovial fluid IL-33 levels were higher in RA than in OA patients, and undetectable in PsA serum and synovial fluid [54]. Another study has demonstrated that neutrophils from patients with RA successfully treated with anti-TNF treatment expressed significantly lower levels of ST2 than patients treated with methotrexate alone [59]. In SLE, one study has shown serum IL-33 levels were significantly increased, compared with healthy controls, but to a lower extent than in patients with RA [60]. The other study reported no change in serum IL-33 levels between controls and SLE patients, but did report a significant increase in sST2 that correlated with SLE disease activity [61].
In murine models of RA, IL-33 mRNA has also been detected in the joints of mice undergoing collagen-induced arthritis (CIA) [56], and in mouse knee joints injected with methylated bovine serum albumin [59]. Furthermore, ST2-/- mice developed attenuated CIA and reduced ex vivo collagen-specific induction of pro-inflammatory cytokines (IL-17, TNFα, and IFNγ), and antibody production [55]. Conversely, treatment with IL-33 exacerbated CIA and elevated production of both pro-inflammatory cytokines and anti-collagen antibodies through a mast cell-dependent pathway. Administration of blocking anti-ST2 antibodies at the onset of CIA also attenuated the severity of disease and reduced joint destruction [56]. This was also associated with reduced IFNγ and IL-17 production. In a model of anti-glucose-6-phosphate isomerase autoantibody-induced arthritis, IL-33 treatment exacerbated disease. Conversely, ST2-/- mice were protected against disease and had reduced expression of articular pro-inflammatory cytokines [62]. The IL-33 effects in this model also appear to be mast cell-dependent as IL-33 failed to increase the severity of the disease in mast cell-deficient mice, and mast cells from wild-type, but not ST2-/- mice restored the ability of ST2-/- recipients to respond. IL-33 has also been shown to chemoattract neutrophils to a knee joint injected with methylated bovine serum albumin [59].
Various rheumatological diseases can have effects on bone including erosion (e.g. RA) and ossification and the formation of new bone (e.g., ankylosing spondylitis and OA). Recently, the role of IL-33 in bone metabolism and remodeling has been studied with conflicting results. Bone structure and metabolism are determined by the formation and activity of osteoclasts and osteoblasts. Mun and co-workers showed that IL-33 can stimulate the formation of multi-nuclear osteoclasts from monocytes, and enhanced expression of osteoclast differentiation factors including TRAF6, nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor [63]. However, in contrast two other studies have shown that IL-33 completely abolished the generation of multinucleated osteoclasts [64] or had no direct effect [65,66].
IL-33 also appears to have direct effects on osteoblast cells. IL-33 expression increases during osteoblast differentiation, and that while ST2-/- mice displayed normal bone formation they had increased bone resorption, thereby resulting in low trabecular bone mass [64]. Furthermore, IL-33 mRNA levels are increased in osteoblasts following treatment with the bone anabolic factors parathyroid hormone or oncostatin M. In addition, IL-33 treatment promoted matrix mineral deposition by osteoblasts in vitro [65]. However, a recent study reports conflicting data that while IL-33 mRNA is present in human osteoblasts, ST2L is not constitutively expressed and IL-33 treatment has no effect on these cells [66]. The reasons for these differences in the biology of IL-33 in osteoclasts and osteoblasts are unclear at present but may reflect different cell culture conditions and differentiation protocols used. In summary, IL-33 appears to have pro-inflammatory effects in various rheumatological diseases activating synovial fibroblasts and mast cells within joints.
Inflammatory skin disorders
Skin and activated dermal fibroblasts contain a high level of IL-33 mRNA expression compared to other tissues and cell types [3]. IL-33 mRNA and protein is also substantially higher in the skin lesions of patients with atopic dermatitis compared with non-inflamed skin samples [67], and in affected psoriatic skin compared to healthy skin [68,69]. Elevated serum IL-33 levels have also been detected in patients with systemic sclerosis, and levels correlated positively with the extent of skin sclerosis [70]. Furthermore, subcutaneous administration of IL-33 can induce IL-13-dependent fibrosis of skin in murine models [71]. Recently, it was shown that ST2-/- mice exhibited reduced cutaneous inflammatory responses compared to WT mice in a phorbol ester-induced model of skin inflammation [69]. Furthermore, intradermal injections of IL-33 into the ears of mice induced a psoriasis-like inflammatory lesion that was partially dependent on mast cells.
In addition, IL-33 expression was induced in pericytes in an experimental model of wound healing in rat skin [72]. Surprisingly, IL-33 has also been shown to induce cutaneous hypernociception in mice, a phenomenon traditionally associated with Th1 responses [73]. Collectively, these results demonstrate that IL-33 may play a role in various inflammatory skin disorders (Figure (Figure22).
Schematic representation of the potential pro-inflammatory role of IL-33 in normal skin and in skin inflammation (atopic dermatitis and psoriasis). Damage to the skin such as by scratching in response to an allergen and inflammation lead to cell necrosis …
Inflammatory bowel disease (IBD)
IBD is a group of chronic inflammatory conditions of the colon and small intestine, including ulcerative colitis (UC) and Crohn’s disease, resulting from dysregulated immune responses. Several studies report an upregulation of IL-33 mRNA in human biopsy specimens from untreated or active UC patients compared to controls [72,74-77]. The main sites of UC IL-33 expression were myofibroblasts and epithelial cells. Similarly, ST2 transcripts have been detected in mucosa samples from patients with active UC [74,75]. However, although Carriere and co-workers demonstrated expression of IL-33 in endothelial cells of Crohn’s disease intenstine [11], subsequent studies have failed to demonstrate a significant role for IL-33 in Crohn’s disease [72,74,76]. Serum IL-33 and sST2 levels were elevated in UC patients compared with controls, while anti-TNF treatment decreased circulating IL-33 and increased sST2, thus favorably altering the ratio of the cytokine with its decoy receptor [74]. However, in other studies serum concentrations of IL-33 were low or did not differ between UC patients and healthy controls [75,78].
Several murine studies highlight a role for IL-33 in innate-type immunity in the gut. Mice treated with IL-33 displayed epithelial hyperplasia and eosinophil/neutrophil infiltration in the colonic mucosa [3]. Furthermore, in a murine model of T-cell independent dextran sodium sulphate (DSS)-induced colitis IL-33-/- mice had enhanced viability, compared to wild-type controls [19]. In a related study macrophage-specific transgenic mice that express a truncated TGF-β receptor II under control of the CD68 promoter (CD68TGF-βDNRII) and subjected to the DSS model of colitis display an impaired ability to resolve colitic inflammation but also an increase in IL-33+ macrophages compared to controls [79]. In addition, IL-33 mRNA is upregulated in the ilea and correlates with disease severity in a murine model of Th1/Th2-mediated enteritis, and induced IL-17 production from mesenteric lymph node cells stimulated ex vivo [74]. In summary, the IL-33/ST2 pathway may be an important regulator of UC, but be of less importance in Crohn’s disease.
Central nervous system (CNS) inflammation
Basal IL-33 mRNA levels are extremely high in the brain and spinal cord [3], and are elevated under conditions such as experimental subarachnoid hemorrhage [1]. Furthermore, expression of IL-33 in glial and astrocyte cultures is increased by Toll-like receptor ligands [80]. Treatment with IL-33 induces proliferation of microglia and enhances production of pro-inflammatory cytokines, such as IL-1β and TNFα, as well as the anti-inflammatory cytokine IL-10 [81]. It also enhances chemokines and nitric oxide production and phagocytosis by microglia. In mice, IL-33 levels and activity were increased in brains infected with the neurotropic virus Theiler’s murine encephalomyelitis virus [80]. Finally, a transcriptional analysis of brain tissue from patients with Alzheimer’s disease revealed that IL-33 expression was decreased compared to control tissues [82]. This study also demonstrated that 3 polymorphisms within the IL-33 gene resulting in a protective haplotype were associated with risk of Alzheimer’s disease [82]. This data is supported by a study in Chinese population with evidence that genetic variants of IL-33 affect susceptibility to Alzheimer’s disease [83]. Furthermore, cell-based assays demonstrate that IL-33 can decrease secretion of β-amyloid peptides [82]. Thus, IL-33 may have a role in regulating pathophysiology and inflammatory responses in the CNS.
Cancer
Although early reports document the expression of ST2 on leukaemic cell lines and on T cell lymphomas of patients [84,85], very few studies have addressed the role of IL-33/ST2 signaling on anti-tumor immune responses, tumor growth and/or metastasis. However, a recent study demonstrated that ST2-/- mice with mammary tumors have attenuated tumor growth and metastasis, with increased circulating levels of pro-inflammatory cytokines and activated NK and CD8+ T cells [86]. Furthermore, IL-33 induces proliferation, migration, and morphologic differentiation of endothelial cells, consistent with an effect on angiogenesis [87]. In addition, IL-33 expression is present in endothelial cells of healthy organs but is strikingly absent from those in tumors [88]. Therefore, IL-33 may be an important mediator in tumor escape from immune control and in tumor angiogenesis and thus warrants further investigation.
Cardiovascular (CV) disease
IL-33 was initially found in the nucleus of the high endothelial venules (HEV) of secondary lymphoid tissues [2]. More recently, IL-33 expression has been reported in coronary artery smooth muscle cells [3], coronary artery endothelium [89], non-HEV endothelial cells [88,90], adipocytes [66,91], and in cardiac fibroblasts suggesting that IL-33 may play a role in various CV disorders [92].
sST2 as a CV biomarker
This concept is supported by the clinical finding that the IL-33 decoy receptor sST2 was elevated in serum early after acute myocardial infarction (AMI), and correlated with creatine kinase and inversely correlated with left ventricular ejection fraction [93]. Since this primary observation several studies have since demonstrated the prognostic value of measuring serum sST2 in various CV diseases, showing that high baseline levels of sST2 were a significant predictor of CV mortality and heart failure (HF) (Table (Table1).1).
Taken together, these studies indicate that sST2 has the potential to be a predictive CV biomarker in patients with AMI, HF and dyspnea. Thus far, serum or plasma IL-33 has not been measured in CV disease. While levels are elevated in atopy [67], and some rheumatological diseases [57,58], the levels in CV disease are likely to be low (possibly due to elevated sST2 levels) and difficult to measure with currently available assays.
However, recent studies have highlighted the development of multiplex assays to measure low abundance IL-33 in serum or plasma and warrant further investigation in the context of CV disease [94]. In summary, sST2 shows promise as a biomarker predictive of mortality in several CV disorders.
Studies examining sST2 in serum/plasma of patients with CV disease
Cardiac fibrosis and hypertrophy
Studies in animal models suggest that sST2 is more than just a marker in CV disease and implicate IL-33/ST2 signaling as an important protective pathway in various CV diseases. In a model of pressure overload IL-33 treatment reduced cardiac hypertrophy and fibrosis, and improved survival following transverse aortic constriction in wild-type but not ST2-/- mice [92].
sST2 blocked the anti-hypertrophic effects of IL-33, indicating that sST2 functions in the myocardium as a soluble decoy receptor of IL-33. IL-33 can also reduce cardiomyocyte apoptosis, decrease infarct and fibrosis, and improve ventricular function in vivo via suppression of caspase-3 activity and increased expression of the ‘inhibitor of apoptosis’ family of proteins [95].
The protective effects of IL-33 may be limited by the neurohormonal factor endothelin-1, which increased expression of sST2 and inhibited IL-33 signaling through p38 MAP Kinase [96].
Atherosclerosis
During atherosclerosis immune cells such as monocytes, T cells and mast cells infiltrate plaques within the intima of the arterial wall [97]. The disease appears to be driven by a Th1 immune response with cytokines such as IL-12 and IFNγ inducing pathogenesis [98,99]. Thus, it was hypothesized that IL-33 may have protective effects during atherosclerosis by inducing a Th1-to-Th2 switch of immune responses.
Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) have TIR intracellular domains that engage two main signaling pathways, via the TIR-containing adaptors MyD88 (which is not used by TLR3) and TRIF (which is used only by TLR3 and TLR4). Extensive studies in inbred mice in various experimental settings have attributed key roles in immunity to TLR- and IL-1R-mediated responses, but what contribution do human TLRs and IL-1Rs actually make to host defense in the natural setting?
Evolutionary genetic studies have shown that human intracellular TLRs have evolved under stronger purifying selection than surface-expressed TLRs, for which the frequency of missense and nonsense alleles is high in the general population. Epidemiological genetic studies have yet to provide convincing evidence of a major contribution of common variants of human TLRs, IL-1Rs, or their adaptors to host defense.
Clinical genetic studies have revealed that rare mutations affecting the TLR3-TRIF pathway underlie herpes simplex virus encephalitis, whereas mutations in the TIR-MyD88 pathway underlie pyogenic bacterial diseases in childhood. A careful reconsideration of the contributions of TLRs and IL-1Rs to host defense in natura is required.
Human TLRs and IL-1Rs in Host Defense: Natural Insights from Evolutionary, Epidemiological, and Clinical Genetics
Annual Review of Immunology
Vol. 29: 447-491 (Volume publication date April 2011)
First published online as a Review in Advance on January 3, 2011
DOI: 10.1146/annurev-immunol-030409-101335
Jean-Laurent Casanova,1,2 Laurent Abel,1,2 and Lluis Quintana-Murci3
1St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10021; email: casanova@rockefeller.edu
2Laboratory of Human Genetics of Infectious Diseases, INSERM U980, University Paris Descartes, Necker Medical School, Paris, France, EU
3Human Evolutionary Genetics, CNRS URA 3012, Institut Pasteur, Paris, France, EU
Roles of Epithelial Cell–Derived Type 2–Initiating Cytokines in Experimental Allergic Conjunctivitis
Yosuke Asada,1,2 Susumu Nakae,2 Waka Ishida,3 Kanji Hori,1 Jobu Sugita,1 Katsuko Sudo,4
Ken Fukuda,3 Atsuki Fukushima,3 Hajime Suto,5,6 Akira Murakami,1 Hirohisa Saito,7
Nobuyuki Ebihara,1 and Akira Matsuda1
1Laboratory of Ocular Atopic Diseases, Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan
2Frontier Research Initiative, Institute of Medical Science, University of Tokyo, Tokyo, Japan
3Department of Ophthalmology, Kochi University School of Medicine, Nangoku, Japan
4Animal Research Center, Tokyo Medical University, Tokyo, Japan
5Department of Dermatology, Juntendo University School of Medicine, Tokyo, Japan
6Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan
7Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
Intravenous Immunoglobulin Treatment in Humans Suppresses Dendritic Cell Function via Stimulation of IL-4 and IL-13 Production
Angela S. W. Tjon*, Rogier van Gent*, Haziz Jaadar*, P. Martin van Hagen†, Shanta Mancham*, Luc J. W. van der Laan‡, Peter A. W. te Boekhorst§, Herold J. Metselaar* and Jaap Kwekkeboom*
Author Affiliations
*Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
†Department of Internal Medicine and Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
‡Department of Surgery, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands; and
- Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
Address correspondence and reprint requests to Dr. Jaap Kwekkeboom, Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Room Na-1009, 3015 CE Rotterdam, The Netherlands. E-mail address: j.kwekkeboom@erasmusmc.nl
Abstract
High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33–Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling.
The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels.
Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment.
Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.
- IgA. High levels of IgA may mean that monoclonal gammopathy of unknown significance (MGUS) or multiple myeloma is present. Levels of IgA also get higher in some autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), and in liver diseases, such as cirrhosis and long-term (chronic) hepatitis.
- IgG. High levels of IgG may mean a long-term (chronic) infection, such as HIV, is present. Levels of IgG also get higher in IgG multiple myeloma, long-term hepatitis, and multiple sclerosis (MS). In multiple myeloma, tumor cells make only one type of IgG antibody (monoclonal); the other conditions cause an increase in many types of IgG antibodies (polyclonal).
- IgM. High levels of IgM can mean macroglobulinemia, early viral hepatitis, mononucleosis, rheumatoid arthritis, kidney damage (nephrotic syndrome), or a parasite infection is present. Because IgM antibodies are the type that form when an infection occurs for the first time, high levels of IgM can mean a new infection is present. High levels of IgM in a newborn mean that the baby has an infection that started in the uterus before delivery.
- IgD. How IgD works in the immune system is not clear. A high level may mean IgD multiple myeloma is present. IgD multiple myeloma is much less common than IgA or IgG multiple myeloma.
- IgE. A high level of IgE can mean a parasite infection is present. Also, high levels of IgE often are found in people who have allergic reactions, asthma, atopic dermatitis, some types of cancer, and certain autoimmune diseases. In rare cases, a high level of IgE may mean IgE multiple myeloma.
