AIM2 in regulatory T cells restrains autoimmune diseases

Chou, Wei-Chun; Guo, Zengli; Guo, Hao; Chen, Liang; Zhang, Ge; Liang, Kaixin; Xie, Ling; Tan, Xianming; Gibson, Sara A.; Rampanelli, Elena; Wang, Yan; Montgomery, Stephanie A.; Brickey, W. June; Deng, Meng; Freeman, Leslie; Zhang, Song; Su, Maureen A.; Chen, Xian; Wan, Yisong Y.; Ting, Jenny P.Y.

doi:10.1038/s41586-021-03231-w

Cited by 98 publications

(90 citation statements)

References 37 publications

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“…Next, we tested the AIM2 inflammasome. Congruent with recent reports (13,29), we found AIM2 to be protective in EAE, as demonstrated by more severe disease in Aim2 -/mice predominantly after disease peak, when induced with a low dose adjuvant (50 μg Mtb/mouse) (Fig. 7C, D).…”

Section: Aim2 Facilitates Inflammasome Activation In the Cns During Eaesupporting

confidence: 88%

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

Barclay

Deerhake

Inoue

et al. 2021

Preprint

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Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.

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Section: Aim2 Facilitates Inflammasome Activation In the Cns During Eaesupporting

confidence: 88%

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

Barclay

Deerhake

Inoue

et al. 2021

Preprint

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“…A recently published paper in Nature shows that AIM2 is expressed at a much higher level in Treg cells than in innate immune cells, in both mice and humans, and can be induced by TGFβ. A high level of AIM2 can maintain the normal function of Treg cells and protect mice from developing autoimmune encephalomyelitis and inflammatory colitis by reducing AKT–mTOR signaling 43 . These findings indicating the inflammasome‐independent role of AIM2 in adaptive cells differ from AIM2's classic function in innate immunity.…”

Section: Role Of Aim2 In Immune Cellsmentioning

confidence: 94%

“…A high level of AIM2 can maintain the normal function of Treg cells and protect mice from developing autoimmune encephalomyelitis and inflammatory colitis by reducing AKT–mTOR signaling. 43 These findings indicating the inflammasome‐independent role of AIM2 in adaptive cells differ from AIM2's classic function in innate immunity.…”

Section: Role Of Aim2 In Immune Cellsmentioning

confidence: 98%

The complex role of AIM2 in autoimmune diseases and cancers

Zhu

Zhao

Chang

et al. 2021

Immunity Inflam & Disease

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Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)‐inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double‐stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent‐manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome‐dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS‐STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non‐small‐cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.

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“…Intratumoral Treg cells also actively rewire transcription factor SREBP-dependent de novo lipid biosynthesis, contributing to the TCR-induced functional maturation and induction of PD-1 expression ( 20 ). In the case of autoimmune disease, the OXPHOS of lipids is promoted by the DNA-binding inflammasome receptor AIM, which attenuates Akt phosphorylation, mTOR and Myc signaling ( 29 ). Interestingly, more recent work using tissue-resident Treg cells from patients with multiple sclerosis reveals that oleic acid is necessary to counteract the negative effects of upregulated glucose uptake ( 30 ).…”

Section: An Overview Of Metabolic Reprogramming In Treg Cellsmentioning

confidence: 99%

Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells

et al. 2021

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Forkhead box protein 3 (Foxp3+)-expressing regulatory T (Treg) cells are a unique CD4+T cell subset that suppresses excessive immune responses. The epigenetic plasticity and metabolic traits of Treg cells are crucial for the acquisition of their phenotypic and functional characteristics. Therefore, alterations to the epigenetics and metabolism affect Treg cell development and function. Recent evidence reveals that altering the metabolic pathways and generation of metabolites can regulate the epigenetics of Treg cells. Specifically, some intermediates of cell metabolism can directly act as substrates or cofactors of epigenetic-modifying enzymes. Here, we describe the metabolic and epigenetic features during Treg cell development, and discuss how metabolites can contribute to epigenetic alterations of Treg cells, which affects Treg cell activation, differentiation, and function.

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AIM2 in regulatory T cells restrains autoimmune diseases

Cited by 98 publications

References 37 publications

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

The complex role of AIM2 in autoimmune diseases and cancers

Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells

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