mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome

Huang, Zhengping; You, Xiaomeng; Chen, Liang; Du, Yongmei; Brodeur, Kailey; Jee, Hyuk; Wang, Qiang; Linder, Grace; Darbousset, Roxane; Cunin, Pierre; Chang, Margaret H.; Wactor, Alexandra; Wauford, Brian M.; Todd, Marc J. C.; Wei, Kevin; Liu, Ying; Levescot, Anaïs; Iwakura, Yoichiro; Pascual, Virginia; Baldwin, Nicole; Quartier, Pierre; Li, Tianwang; Gianatasio, Maria T.; Henderson, Lauren A.; Sykes, David B.; Mellins, Elizabeth; Canna, Scott; Charles, Julia F.; Nigrovic, Peter A.; Lee, Pui Y.

doi:10.1038/s41467-022-34480-6

Cited by 23 publications

(7 citation statements)

References 66 publications

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“…Rapamycin, an inhibitor of mTORC1, ameliorates most of these symptoms in the IL1RN deficiency model and fully prevented hemophagocytosis in Tsc2 KO animals. Interestingly, the activation of mTOR pathway is also seen in the repeated TLR-9 model, and rapamycin significantly ameliorates MAS symptoms (cytopenia, hyperferritinemia, hepatosplenomegaly, and plasma IFN-γ levels) [ 72 ]. The precise molecular mechanisms of how mTOR pathway could affect the pathophysiology of SJIA and MAS have not been clarified, but these overall results suggest that mTOR pathway, specifically in monocytes, could be a candidate treatment target.…”

Section: Animal Models For Mas and Sjiamentioning

confidence: 99%

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Inoue

Schulert

2023

Arthritis Res Ther

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Macrophage activation syndrome (MAS) is a life-threatening complication of pediatric rheumatic diseases, occurring most commonly in children with systemic juvenile idiopathic arthritis (SJIA). Despite several classes of currently available treatment options for SJIA, including biologic agents targeting IL-1 or IL-6, there remain severe cases suffering from refractory disease and recurrent MAS. The phenotype of MAS is similar to hemophagocytic lymphohistiocytosis (HLH), but the underlying pathophysiology of MAS complicating SJIA or other disorders has not been fully clarified. These facts make it challenging to develop and utilize animal models to study MAS. To date, there is no “perfect” model replicating MAS, but several models do demonstrate aspects of SJIA and/or MAS. In this review, we examine the proposed animal models of SJIA and MAS, focusing on how they reflect these disorders, what we have learned from the models, and potential future research questions. As we better understand the key features of each, animal models can be powerful tools to further define the pathophysiology of SJIA and MAS, and develop new treatment targets and strategies.

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Section: Animal Models For Mas and Sjiamentioning

confidence: 99%

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Inoue

Schulert

2023

Arthritis Res Ther

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“…Because the CD38 + HLA-DR + T and NK cells were highly proliferative and metabolically active with enhanced mTORC1 signaling according to our scRNA-Seq data, we tested the effect of the mTOR inhibitor rapamycin. Regulation of immunometabolism by mTORC1 governs effector T cell function, and overt activation of this pathway was shown to cause features of SD and MAS in a murine model ( 38 ). Rapamycin attenuated the expansion of CD38 + HLA-DR + T and NK cells induced by IFN-α2 and IL-15, although the degree of inhibition appeared mild compared with JAK inhibitors, and statistical significance was borderline ( P = 0.06 to 0.07).…”

Section: Resultsmentioning

confidence: 99%

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome

Huang,

Brodeur,

Chen

et al. 2023

Journal of Clinical Investigation

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BACKGROUND Macrophage activation syndrome (MAS) is a life-threatening complication of Still’s disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS. METHOD We profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies. RESULTS Bulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38 + HLA-DR + cells within CD4 + T cell, CD8 + T cell, and NK cell populations. CD38 + HLA-DR + lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38 + HLA-DR + lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38 + HLA-DR + lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 — both elevated in MAS patients — synergistically augmented the generation of CD38 + HLA-DR + lymphocytes, while Janus kinase inhibition mitigated this response. CONCLUSION MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38 + HLA-DR + cycling lymphocytes that produce IFN-γ.

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“…Another study showed that activation of mTORC1 pathways is required for the development of macrophage activation syndrome and hemophagocytosis in a murine model of Still's disease [26]. This finding may explain why patients with MKD, an autoinflammatory disease driven by metabolic alterations, are at an increased risk of developing MAS compared with other autoinflammatory conditions.…”

Section: The Mtor Pathwaymentioning

confidence: 98%

Update on autoinflammatory diseases

Ashari

Hausmann

Dedeoğlu

2023

Current Opinion in Rheumatology

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Purpose of review Although the concept of systemic autoinflammatory diseases (SAIDs) is still very young, our knowledge about them is exponentially growing. In the current review, we aim to discuss novel SAIDs and autoinflammatory pathways discovered in the last couple of years. Recent findings Advances in immunology and genetics have led to the discovery of new pathways involved in autoinflammation, as well as several new SAIDs, including retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache (ROSAH syndrome), vacuoles, E1 enzyme, X-linked autoinflammatory somatic (VEXAS) syndrome, TBK1 deficiency, NEMO deleted exon 5 autoinflammatory syndrome (NDAS), and disabling pansclerotic morphea. Progress in immunobiology and genetics has also brought forth novel treatments for SAIDs. Personalized medicine has made significant progress in areas such as cytokine-targeted therapies and gene therapies. However, much work remains, especially in measuring and improving the quality of life in patients with SAIDs. Summary In the current review, we discuss the novelties in the world of SAIDs, including mechanistic pathways of autoinflammation, pathogenesis, and treatment. We hope this review helps rheumatologists to gain an updated understanding of SAIDs.

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mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome

Cited by 23 publications

References 66 publications

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome

Update on autoinflammatory diseases

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