Inhibition of interleukin‐33 signaling attenuates the severity of experimental arthritis

Palmer, Gaby; Talabot-Ayer, Dominique; Lamacchia, Céline; Toy, Dean; Seemayer, Christian A.; Viatte, Sébastien; Finckh, Axel; Smith, Dirk E.; Gabay, Cem

doi:10.1002/art.24305

Cited by 287 publications

(289 citation statements)

References 44 publications

(32 reference statements)

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“…Several immunohistochemical experiments showed that IL-33 is located in the nucleus of endothelial, epithelial and fibroblast cells [21,22,29], where, like IL-1α, it may exert a transcriptional activity [29].…”

Section: Discussionmentioning

confidence: 99%

“…Mice administered intra-articularly with bovine serum albumin exhibited hypernociception which was blocked by sST2 [33]. In addition, IL-33 was recently shown to exacerbate antigen-induced arthritis by activating bone marrow-derived mast cells [34], and administration of a blocking anti-ST2 antibody attenuated the severity of collagen-induced arthritis [22,35].…”

Section: Introductionmentioning

confidence: 99%

“…IL-33 appears to be predominantly expressed in vivo in endothelial and epithelial cells [20,21], but IL-33 expression may be induced by inflammatory signals in other cell types [11,22]. Cell targets of IL-33 include polarized Th2 cells [11,23,24], mast cells [15,25], basophils [24,26], and dendritic cells [27,28].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, IL-33 has been first localized in the nucleus of endothelial cells, most notably within heterochromatin subdomains and mitotic chromosomes, where it may repress transcription [29]. Subsequently, IL-33 has been identified in the nucleus of epithelial cells [21], synovial fibroblasts [22], and monocytes [30]. Finally, it has been recently suggested that IL-33 might function as an "alarmin", being secreted during cell necrosis, to initiate immune responses [21,31].…”

Section: Introductionmentioning

confidence: 99%

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IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

et al. 2011

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1 IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodelingsuggested that expression of IL-33, in contrast to that of IL-1β, is not repressed by PPARγ, likely explaining why IL-33, but not IL-1β, is expressed in adipocytes. The IL-33 receptor ST2L is not constitutively expressed in human bone marrow stromal cells, osteoblasts or CD14-positive monocytes, and IL-33 has no effect on these cells. In addition, although ST2L mRNA is induced by TNF-α and IL-1β in bone marrow stromal cells, IL-33 has the same effects as TNF-α and IL-1β, and, therefore, the biological activity of IL-33 may be redundant in this system. In agreement with this hypothesis, MC3T3-E1 osteoblast-like cells constitutively express ST2L mRNA, and in these cells IL-33 and TNF-α/IL-1β similarly decrease osteocalcin RNA levels in these cells. In conclusion, our results suggest that IL-33 has no direct effects on normal bone remodeling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

et al. 2011

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“…IL-33 [previously known as nuclear factor from high endothelial venule or NF-HEV (4,5)], is a chromatin-associated nuclear cytokine from the IL-1 family (6, 7), which has been linked to important diseases (8)(9)(10), including asthma (11), rheumatoid arthritis (12,13), ulcerative colitis (14), and cardiovascular diseases (15).…”

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confidence: 99%

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

Lefrançais

Roga

Gautier

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

506

464

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Interleukin-33 (IL-33) (NF-HEV) is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to important diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and cardiovascular diseases. IL-33 signals through the ST2 receptor and drives cytokine production in type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes), T-helper (Th)2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer T (iNKT), and natural killer (NK) cells. We and others recently reported that, unlike IL-1β and IL-18, full-length IL-33 is biologically active independently of caspase-1 cleavage and that processing by caspases results in IL-33 inactivation. We suggested that IL-33, which is released upon cellular damage, may function as an endogenous danger signal or alarmin, similar to IL-1α or high-mobility group box 1 protein (HMGB1). Here, we investigated the possibility that IL-33 activity may be regulated by proteases released during inflammation. Using a combination of in vitro and in vivo approaches, we demonstrate that neutrophil serine proteases cathepsin G and elastase can cleave full-length human IL-33 1-270 and generate mature forms IL-33 , and IL-33 . These forms are produced by activated human neutrophils ex vivo, are biologically active in vivo, and have a ∼10-fold higher activity than full-length IL-33 in cellular assays. Murine IL-33 is also cleaved by neutrophil cathepsin G and elastase, and both fulllength and cleaved endogenous IL-33 could be detected in the bronchoalveolar lavage fluid in an in vivo model of acute lung injury associated with neutrophil infiltration. We propose that the inflammatory microenvironment may exacerbate disease-associated functions of IL-33 through the generation of highly active mature forms.innate immunity | inflammatory protease | serine protease inhibitor | alveolar epithelium C ytokines of the IL-1 family (IL-1α, IL-1β, IL-18) play a major role in inflammatory, infectious, and autoimmune diseases (1-3). IL-33 [previously known as nuclear factor from high endothelial venule or NF-HEV (4, 5)], is a chromatin-associated nuclear cytokine from the IL-1 family (6, 7), which has been linked to important diseases (8-10), including asthma (11), rheumatoid arthritis (12, 13), ulcerative colitis (14), and cardiovascular diseases (15).IL-33 signals through the ST2 receptor (4), a member of the IL-1 receptor family, which is expressed (or induced) on various immune cell types, including mast cells, basophils, eosinophils, Thelper (Th)2 lymphocytes, invariant natural killer T (iNKT) and natural killer (NK) cells, macrophages, dendritic cells, and neutrophils (8-10). IL-33 stimulation of ST2 on Th2 cells induces secretion of the Th2 cytokines IL-5 and IL-13 (4, 16). Recently, IL-33 has been shown to drive production of extremely high amounts of these Th2 cytokines by type 2 innate lymphoid cells (ILCs) (natural helper cells, nuocytes, innate helper 2 cells), which play important roles in innate immune responses, after helminth infec...

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Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell–specific interleukin‐1 receptor antagonist

Lamacchia¹,

Palmer²,

Seemayer³

et al. 2010

Arthritis & Rheumatism

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Objective. The balance between interleukin-1 (IL-1) and its specific inhibitor, the IL-1 receptor antagonist (IL-1Ra), plays a major role in the development of arthritis. The purpose of this study was to investigate the role of IL-1Ra produced specifically by myeloid cells in the control of collagen-induced arthritis (CIA) by using myeloid cell-specific IL-1Ra-deficient mice (IL1Ra ⌬M ). Methods. IL-1Ra⌬M mice were generated by using the loxP/Cre recombinase system. CIA was induced in IL-1Ra ⌬M mice and littermate control mice by a single immunization with bovine type II collagen (CII) in Freund's complete adjuvant. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (DLN) cell responses were examined ex vivo, and ankle extracts were used in the quantification of cytokines and chemokines.Results. Clinical and histopathologic evaluations revealed an early disease onset and a severe form of CIA in IL-1Ra ⌬M mice. This was characterized by increased production of interferon-␥ (IFN␥) and IL-17 by CIIstimulated DLN cells. We also observed that the CIIspecific CD4؉ T cell response shifted in vivo, from a dominant Th1 response early in the course of the arthritis to the presence of both Th1 and Th17 cytokines later in the disease course. Interestingly, IL-1Ra levels were higher in the arthritic joints of IL-1Ra ⌬M mice as compared with the controls, indicating that nonmyeloid cells strongly contribute to the local production of IL-1Ra. However, this enhanced IL-1Ra production was not sufficient to limit joint inflammation and tissue damage.Conclusion. Our results suggest that myeloid cell-derived IL-1Ra plays a critical role in the control of the development and the severity of CIA by modulating Th1 and Th17 responses in lymphoid organs.

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Inhibition of interleukin‐33 signaling attenuates the severity of experimental arthritis

Cited by 287 publications

References 44 publications

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell–specific interleukin‐1 receptor antagonist

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