STTT Central South University Lu Qianjin and other teams found potential therapeutic targets for systemic lupus erythematosus

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Deletion 2 in iNature melanoma (AIM2) was originally identified as a tumor suppressor for melanoma.
AIM2 is a member of the interferon (IFN) inducible PYHIN protein family
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Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in B cells from lupus patients
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So far, the inflammasome-independent function of AIM2 in B cells remains unclear
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On September 14, 2021, a joint communication between Lu Qianjin and Wu Haijing of Central South University was published online in Signal Transduction and Targeted Therapy (IF=18.
19) entitled "AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1–Bcl-6 Axis-mediated B-cell differentiation" research paper, which reports the increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and memory B cells and plasma cells from circulation and skin lesions in patients with lupus
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Conditionally knocking out AIM2 in B cells will reduce the frequency of CD19+ B cells in lymph nodes and spleen, and inhibit the production of IgG1 antibodies induced by KLH
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In a mouse model of lupus induced by pristane, AIM2 deficiency in B cells reduces lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablasts, and plasma cells
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In addition, the loss of AIM2 in human B cells resulted in increased Blimp-1 expression and decreased Bcl-6 expression
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However, the silencing of Blimp-1 and Bcl-6 had no significant effect on the expression of AIM2, indicating that AIM2 may be an upstream regulator of Blimp-1 and Bcl-6
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In addition, IL-10 was found to up-regulate AIM2 expression through DNA demethylation
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In conclusion, the results of this study show that AIM2 is highly expressed in B cells of patients with lupus and promotes B cell differentiation by regulating the Bcl-6-Blimp-1 axis, providing a new target for SLE treatment
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Deletion in melanoma 2 (AIM2) was originally identified as a tumor suppressor for melanoma.
AIM2 is a member of the interferon (IFN) inducible PYHIN protein family
.

Among immune cells, AIM2 is mainly observed in innate immunity, such as macrophages and dendritic cells.
Its function is to sense pathogen-related or host-derived cytoplasmic dsDNA and recruit other inflammasome components, such as ASC and pro- caspase-1 and induce the formation of caspase-dependent inflammasomes
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AIM2-inflammasome can further promote the production of IL-18 and IL-1β or gasdermin-D (GSDMD)-mediated pyrolysis
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In addition, the inflammasome-independent function of AIM2 is also related to regulation
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However, whether AIM2 exerts a non-inflammasome-dependent effect on immune cells, especially adaptive immune cells, remains unclear
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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of large amounts of autoantibodies
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Therefore, B cells, which are the main source of antibodies, are considered to be the main immune cells that cause the immune abnormalities observed in SLE
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In the peripheral circulation, mature B cells are activated by self or foreign antigens, and then differentiate into memory B cells or antibody-producing plasma cells
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After the germinal center (GC) reaction, B cells finally differentiate into plasma cells
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Although memory B cells cannot secrete antibodies, they can further undergo somatic hypermutation (SHM) and/or class switching, and then differentiate into plasma cells after subsequent antigen exposure
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This process is mainly regulated by the B-regulated lymphocyte-induced mature protein 1 (Blimp-1)-Bcl-6 axis
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Blimp-1 (encoded by Prdm1) controls the differentiation of plasma cells
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Bcl-6 is well proven to be a key transcription factor for GC B cell differentiation
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Before differentiation, Blimp-1 is inhibited by Bcl-6
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It has been reported that the increased expression of Prdm1 may be due to the release of Bcl-6 binding to histone deacetylase (HDAC), thereby increasing the level of histone acetylation in the promoter region of Prdm1
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Blimp-1 inhibits gene transcription of Bcl6, Pax5, and Spib, which in turn inhibit Blimp-1 transcription and GCB and plasma cell differentiation
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Therefore, the Bcl-6-Blimp-1 axis controls B cell differentiation
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Here, the study first described the increase in AIM2 levels in human tonsil memory and GC B cells, as well as memory B cells and plasma cells from the peripheral blood of patients with lupus
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In order to further explore the function of AIM2 in B cells, this study constructed CD19 conditional knockout AIM2 mice
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The loss of AIM2 in B cells reduces the production of antibodies induced by KLH and improves lupus symptoms
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In terms of mechanism, it is found that IL-10 up-regulates the expression of AIM2 through DNA demethylation, and that AIM2 directly binds to Blimp-1 and Bcl-6 and regulates their expression
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The findings of this study may provide a new target for the treatment of lupus
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