AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1–Bcl-6 axis-mediated B-cell differentiation

Yang, Ming; Long, Di; Hu, Longyuan; Zhao, Zhixiang; Li, Qianwen; Guo, Yunkai; He, Zhenghao; Zhao, Ming; Lü, Lei; Li, Fen; Long, Hai; Wu, Haijing; Lu, Qianjin

doi:10.1038/s41392-021-00725-x

Cited by 54 publications

(37 citation statements)

References 29 publications

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“…Additionally, in our study Aim2 −/− Rag1 −/− mice clearly exhibited improvement in disease activity, implying that adaptive immune cells are involved in the nephritis of Aim2 −/− mice, despite deficiency of Aim2 in the B cells and T cells of these mice. In light of findings reported by Yang et al (8), it would be interesting to compare Aim2 deficiency in different types of cells among animals in the same facility with SLE development upon pristane injection, because lupus induction is a long process and microbiota may affect disease development.…”

Section: Replymentioning

confidence: 99%

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Meng

2022

Arthritis & Rheumatology

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manifestations, such as lupus nephritis (1). To date, a clear pathogenesis of SLE has not been fully elucidated. Therefore, searching for the mechanisms involved in the development of SLE and targeting potential mechanisms for treatment remain topics of investigation.Absent in Melanoma 2 (AIM2) is a member of the pyrin and hematopoietic interferon (IFN)-inducible nuclear domain proteins. This protein has wide-ranging, propyroptotic properties. Regarding innate immunity, AIM2 serves as a cytoplasmic double-stranded DNA (dsDNA) sensor, regulating the initiation of innate immune responses (2). The recognition of dsDNA by AIM2 results in the assembly of a large multiprotein oligomeric complex known as the inflammasome, which regulates interleukin-1β (IL-1β) and IL-18 generation and induces cell death. In the cytosol, sensing of dsDNA by AIM2 is important for protection against invading pathogens, such as bacteria, viruses, and fungi. Conversely, the response of AIM2 to dsDNA released by damaged host cells may lead to the production of different cytokines that are involved in the pathogenesis of sterile inflammatory diseases, such as skin and kidney diseases. AIM2 contributes to lung tumorigenesis through the inflammasomedependent release of IL-1β and the regulation of mitochondrial dynamics. The AIM2 inflammasome becomes activated in the presence of atherosclerotic plaque, abdominal wall aortic aneurysm, and injured myocardium.To date, the findings of studies on AIM2 in the setting of lupus have been inconsistent. In a recent study by Dr. Lu and colleagues (1), it was found that Aim2 gene-deficient mice developed lupus, demonstrated by high histologic scores and high serum levels of dsDNA, myeloperoxidase, proteinase 3, albumin, and urea nitrogen, after pristane treatment. Increased infiltration of dendritic cells, macrophages, neutrophils, B cells, and T cells as well as high type I IFN signatures were also found in the kidneys of Aim2 gene-deficient mice treated with pristane. Aim2 deficiency resulted in elevated expression of type I IFN-induced genes in the kidneys, suggesting that AIM2 inhibits the development of lupus (1).Similarly, Panchanathan et al predicted that Aim2 deficiency contributed to increased susceptibility to lupus (2). In their study, Aim2 gene-deficient mice had high expression of p202 protein, which correlated with increased expression of IFNβ, STAT1, and IFN-inducible genes (2). In contrast, Huang et al evaluated Aim2 expression in lupus nephritis patients and found that Aim2 was highly expressed in the glomerular cells of patients with lupus nephritis class II (3).Yang et al found that in SLE patients, Aim2 expression was increased in germinal center B cells and plasma cells from peripheral blood, and in tonsil memory and skin lesions (4). Proportions of CD19+ cells were down-regulated in the lymph nodes and spleens of mice with lupus and Aim2 gene-deficient B cells. Aim2 deficiency in B cells attenuated the development of lupus, as shown by reduced glomerulonephritis, lower proportions of LE...

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confidence: 99%

“…With regard to the elevated Aim2 expression in SLE patients and apoptotic DNA-treated BALB/c mice (8,9), it should be noted that the Aim2 gene itself is an ISG whose expression can be induced by IFN. Moreover, as demonstrated in the study by Yang et al, IL-10 can also induce the expression of Aim2 (8).…”

Section: Replymentioning

confidence: 99%

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Meng

2022

Arthritis & Rheumatology

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“…Given the role of NLRP3 inflammasome in maintaining B-cell homeostasis, it has been suggested that the regulation of B-cell inflammasomes is also an important mechanism in SLE. In addition to NLRP3, it has been found that AIM2 is highly expressed in B cells from SLE patients, promoting B-cell differentiation by regulating the Bcl-6–Blimp-1 axis; this provides a novel target for SLE treatment ( 32 ).…”

Section: Inflammasomes Are Involved In the Pathogenesis Of Slementioning

confidence: 99%

Strategies of Targeting Inflammasome in the Treatment of Systemic Lupus Erythematosus

Liu

Tao

2022

Front. Immunol.

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ dysfunction resulting from the production of multiple autoantibodies and adaptive immune system abnormalities involving T and B lymphocytes. In recent years, inflammasomes have been recognized as an important component of innate immunity and have attracted increasing attention because of their pathogenic role in SLE. In short, inflammasomes regulate the abnormal differentiation of immune cells, modulate pathogenic autoantibodies, and participate in organ damage. However, due to the clinical heterogeneity of SLE, the pathogenic roles of inflammasomes are variable, and thus, the efficacy of inflammasome-targeting therapies is uncertain. To provide a foundation for the development of such therapeutic strategies, in this paper, we review the role of different inflammasomes in the pathogenesis of SLE and their correlation with clinical phenotypes and propose some corresponding treatment strategies.

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“…The same research team also recently revealed higher AIM2 expression in memory B cells and plasma cells from the circulation and skin lesions of lupus patients 6 . IL‐10 has a greater capacity than IL‐21 to upregulate AIM2 in B cells by reducing the DNA methylation level of AIM2 6 .…”

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“… 6 Importantly, conditional knockout of Aim2 in B cells attenuates lupus symptoms and reduces T FH , GC B cells and plasma cells in the pristane‐induced lupus model. 6 It is quite fascinating that both T FH cells and B cells adapt to the lupus environment by employing epigenetic regulation via upregulating AIM2, despite their responses to different triggers. Given the specific impact of autoantibody isotype, specificity or affinity to self‐antigens on SLE pathogenesis, 1 it is imperative to evaluate whether AIM2 expression in T FH cells or B cells regulates the antibody class switching and/or affinity maturation.…”

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confidence: 99%

AIMing 2 promote lupus by targeting helpers

Leavenworth

2022

Clinical & Translational Med

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AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1–Bcl-6 axis-mediated B-cell differentiation

Cited by 54 publications

References 29 publications

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Strategies of Targeting Inflammasome in the Treatment of Systemic Lupus Erythematosus

AIMing 2 promote lupus by targeting helpers

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