Enhanced TLR-MYD88 Signaling Stimulates Autoinflammation in SH3BP2 Cherubism Mice and Defines the Etiology of Cherubism

Yoshitaka, Teruhito; Mukai, Tomoyuki; Kittaka, Mizuho; Alford, Lisa M.; Masrani, Salome; Ishida, Shohei; Yamaguchi, Ken; Yamada, Motohiko; Mizuno, Noriyoshi; Olsen, Bjørn R.; Reichenberger, Ernst; Ueki, Yasuyoshi

doi:10.1016/j.celrep.2014.08.023

Cited by 46 publications

(92 citation statements)

References 54 publications

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“…Strikingly, depleting the commensal microbiota with oral antibiotic treatment did not decrease the inflammation in homozygous cherubic mice (Supplemental Figure 9). However, in agreement with a recent study (20), crossing Sh3bp2 KI/KI mice with Myd88 KO/KO mice reduced serum TNF-α to WT levels, demonstrating the involvement of TLR signaling in autoinflammation of homozygous cherubic mice ( Figure 3F). Most importantly, LPSstimulated heterozygous cherubic BMM displayed enhanced signaling activities compared with WT macrophages (Figure 3, C and D), and heterozygous cherubic mice (Sh3bp2…”

Section: Wt/kisupporting

confidence: 79%

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

Prod’homme¹,

Boyer²,

Dubois³

et al. 2015

J. Clin. Invest.

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Section: Wt/kisupporting

confidence: 79%

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

Prod’homme¹,

Boyer²,

Dubois³

et al. 2015

J. Clin. Invest.

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“…Corrective surgery by curettage with or without bone grafting is sometimes performed for extensively enlarged jaws [44]. Generally, such surgical intervention is considered only in severe cases and most of the surgical interventions are performed after puberty when cherubic lesions may become inactive, although mechanisms of the age-dependent phenotype regression in human cherubism patients, but not in cherubism mice, remain to be further elucidated [3]. Age-associated change in immune responses by TLRs [45, 46] might be a cause of the regression [3].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, BMT was effective even in treating fully inflamed Sh3bp2 KI/KI mice, which were not ameliorated with anti-TNF-α therapy in mice and humans [20, 21], suggesting that wild-type BMT also corrected inflammatory cytokine levels other than TNF-α. We have previously reported that cherubism is a hematopoietic disorder of myeloid lineage cells caused by hyperactive macrophages and osteoclasts [3, 18, 22, 52]. Therefore, we assume that replacement of the mutant macrophages and osteoclasts with those carrying wild-type SH3BP2 is a main cause of the improved symptoms in Sh3bp2 KI/KI mice, which resulted in the comprehensive reconstitution of the expression profile of inflammatory cytokines and osteoclast-mediated bone resorption activity in Sh3bp2 KI/KI recipients.…”

Section: Discussionmentioning

confidence: 99%

“…Swelling of submandibular lymph nodes is also observed [2]. Affected children seem normal at birth and manifest the characteristic facial appearance at 2 to 5 years old, and the cherubism lesions usually begin to regress after puberty by mechanisms that may involve Toll-like receptor (TLR)-MYD88 pathway in macrophages [3]. In some severe cases, the lesions expand into the orbital walls or upper airway [4–7], resulting in upward gazing, optic neuropathy [7], or respiratory disturbance [8].…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice

Yoshitaka

Kittaka

Ishida

et al. 2015

Bone

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Cherubism (OMIM#118400) is a genetic disorder in children characterized by excessive jawbone destruction with proliferation of fibro-osseous lesions containing a large number of osteoclasts. Mutations in the SH3-domain binding protein 2 (SH3BP2) are responsible for cherubism. Analysis of the knock-in (KI) mouse model of cherubism showed that homozygous cherubism mice (Sh3bp2KI/KI) spontaneously develop systemic autoinflammation and inflammatory bone loss and that cherubism is a TNF-α-dependent hematopoietic disorder. In this study, we investigated whether bone marrow transplantation (BMT) is effective for the treatment of inflammation and bone loss in Sh3bp2KI/KI mice. Bone marrow (BM) cells from wild-type (Sh3bp2+/+) mice were transplanted to 6-week-old Sh3bp2KI/KI mice with developing inflammation and to 10-week-old Sh3bp2KI/KI mice with established inflammation. Six-week-old Sh3bp2KI/KI mice transplanted with Sh3bp2+/+ BM cells exhibited improved body weight loss, facial swelling, and survival rate. Inflammatory lesions in the liver and lung as well as bone loss in calvaria and mandibula were ameliorated at 10 weeks after BMT compared to Sh3bp2KI/KI mice transplanted with Sh3bp2KI/KI BM cells. Elevation of serum TNF-α levels was not detected after BMT. BMT was effective for up to 20 weeks in 6-week-old Sh3bp2KI/KI mice transplanted with Sh3bp2+/+ BM cells. BMT also ameliorated the inflammation and bone loss in 10-week-old Sh3bp2KI/KI mice. Thus our study demonstrates that BMT improves the inflammation and bone loss in cherubism mice. BMT may be effective for the treatment of cherubism patients.

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“…106 TLR stimulation, either by PAMPs or DAMPs, is generally thought to have a central role in the pathogenesis of autoinflammation. 107 Thus, targeting factors along this axis might represent an approach with broad therapeutic utility if, in the case of TLR-targeting, residual TLR functions are retained for host-defence. Alternatively, direct targeting of DAMPs could offer the advantage of causing few adverse effects, as these molecules are released only after cell stress or damage.…”

Section: Pamps Damps and Tlrsmentioning

confidence: 99%

From bench to bedside and back again: translational research in autoinflammation

et al. 2015

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Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists.

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Enhanced TLR-MYD88 Signaling Stimulates Autoinflammation in SH3BP2 Cherubism Mice and Defines the Etiology of Cherubism

Cited by 46 publications

References 54 publications

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages

Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock-in cherubism mice

From bench to bedside and back again: translational research in autoinflammation

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