JEM | Yang Shuo/Zhou Jiawei/Hu Gang collaborate to reveal the immunological mechanism of inflammasome AIM2 protein-mediated multiple sclerosis

Multiple Sclerosis (MS) is the most important neuroimmuno-inflammatory degenerative disease that causes disability among young adults in the world, and its incidence in my country is also increasing.

The main pathological features of demyelinating diseases of the central nervous system, including the brain, optic nerve, and spinal cord, are clinical symptoms including motor dysfunction, paresthesia, cognitive impairment, and decreased vision.

The disease recurs, once it enters the acute advanced stage, it will seriously affect the quality of life of the patient, and it may even cause permanent disability and bring great pain to the patient.

The pathogenesis of MS has not yet been fully clarified.
Many factors such as genetics, autoimmunity, infection, and environment are known to affect the occurrence of the disease.
At present, the disease cannot be effectively cured, and existing medications can only delay the progression of the disease [1].

In addition, the disease is heterogeneous.
Unlike European and American countries, my country’s MS is mainly of Asian type, and its clinical manifestations are optic neuromyelitis [2, 3].
However, the current first-line drug interferon is not effective in treating MS optic neuritis.
Even after use, it will aggravate the condition [4-6].

Epidemiological analysis also shows that viral infection is a high-risk factor for some MS [7], and it is well known that viral infection can induce a large amount of inflammatory factors such as interferon [8].

Therefore, different types of MS have heterogeneity in their pathogenesis.
Interferon-related antiviral inflammatory signals may be involved in the pathogenesis of types of MS such as Asian type.
The specific molecular regulation mechanism that affects the occurrence of the disease is unknown and needs to be analyzed.Recently, Professor Yang Shuo’s group of Nanjing Medical University, Shanghai Chinese Academy of Sciences’ Brain Science and Intelligent Technology Excellence Innovation Center Researcher Zhou Jiawei’s Group and Nanjing University of Traditional Chinese Medicine Professor Hu Gang’s Group Co-authored an article in the Journal of Experimental Medicine: AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis.

The study found that the inflammasome AIM2 protein inhibits the occurrence of multiple sclerosis through non-inflammasome functions, reveals the immunological mechanism of antiviral inflammatory pathways mediating the pathogenesis of MS, and provides a drug target for the treatment of Asian multiple sclerosis New clues.

In this study, the researchers found through the GEO database that the AIM2 protein, an important member of the inflammasome family, was up-regulated and expressed in the central nervous system of patients with multiple sclerosis.
Both inflammasome-dependent and independent multiple sclerosis mouse models were used to show that Knockout of AIM2 accelerates disease progression, suggesting that it exerts a negative regulatory effect on disease formation and does not depend on inflammasome function.

A public database search showed that AIM2 is highly expressed in central microglia.
The researchers subsequently used bone marrow transplantation and conditional knockout mouse experiments to further prove that AIM2 inhibits the occurrence of multiple sclerosis neuroinflammation in microglia.

Sorting and sequencing of microglia, GO function and KEGG pathway analysis showed that the most important influence of AIM2 in microglia is cGAS-STING-mediated DNA anti-viral inflammation signal.

Subsequent experiments on molecular protein, cellular immunity, and drug intervention research confirmed that AIM2 inhibits the antiviral inflammatory response mediated by cGAS and DNA-PK synergistically by regulating the activation of the DNA-PK-AKT3 signal axis, thereby hindering microglia.
Transition to disease state and neuroinflammation in multiple sclerosis. It is worth noting that in February this year, the Jenny P.
-Y.
Ting research group of the University of North Carolina at Chapel Hill also reported in Nature that AIM2 inhibits the occurrence of multiple sclerosis and other autoimmune diseases through non-inflammatory body function.
The above focuses on its regulatory function in Treg cells [9].
The possible role of AIM2 in T cells still needs to be further clarified in future studies.

At present, more and more studies have suggested that inflammasome molecules perform non-inflammasome functions, especially the dialogue regulation with cGAS-STING antiviral inflammation pathway, indicating that inflammasome proteins may be synergistic and antagonistic to the occurrence of immune inflammation.
Complex impact.

The discovery that AIM2 negatively regulates the antiviral inflammatory effect mediated by cGAS and DNA-PK in this project has brought new inspiration to the study of the mutual regulation of inflammatory pathways.

In summary, the findings of the above work provide us with new insights into the immunological regulatory mechanisms of the pathogenesis of different types of MS, and at the same time provide new clues for the development of therapeutic drug targets for heterogeneous multiple sclerosis.

Professor Yang Shuo’s research group of Nanjing Medical University has been mainly engaged in the research of innate immunity and inflammatory disease occurrence and intervention target discovery in recent years.
The related work is the first author in Nat Immunol, Mol Cell, J.
Exp.
Med and Sci Adv and other journals.
Published on.

The research group is now openly recruiting 1-2 post-doctoral researchers engaged in research on immunity, drug structure, and bioinformatics.

Post-doctorate will be engaged in cutting-edge research in the field during the post-doctorate period, with generous salaries and good career advancement space.

Resume delivery (If you are interested, please integrate your resume and scientific research level certification data and send it as a PDF file): https://jinshuju.
net/f/ZqXwZt or scan the QR code to submit the original resume link: https://rupress.
org /jem/article-standard/218/5/e20201796/211880/AIM2-controls-microglial-inflammation-to-prevent Plate maker: Eleven References 1.
Lassmann, H.
, J.
Van Horssen, and D.
Mahad, Progressive multiple sclerosis: pathology and pathogenesis.
Nature Reviews Neurology, 2012.
8(11): p.
647-656.
2.
Kira, Ji, Neuromyelitis optica and Asian phenotype of multiple sclerosis.
Annals of the New York Academy of Sciences, 2008.
1142 (1): p.
58-71.
3.
Lai, C.
, et al.
, Neuromyelitis optica antibodies in patients with severe optic neuritis in China.
Journal of Neuro-Ophthalmology, 2011.
31(1): p.
16-19.
4.
Hu Xueqiang and Wang Yuge, Progress in the treatment of multiple sclerosis and neuromyelitis optica.
Clinical Journal of Practical Hospital, 2009.
006(003): p.
5-8.
5.
Shimizu, J.
, et al.
, IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum.
Neurology,2010.
75(16): p.
1423-1427.
6.
Kim, S.
-H.
, et al.
, Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Multiple Sclerosis Journal, 2012.
18(10): p.
1480- 1483.
7.
Ascherio, A.
and KL Munger, Epstein–Barr virus infection and multiple sclerosis: a review.
Journal of Neuroimmune Pharmacology, 2010.
5(3): p.
271-277.
8.
Chen, K.
, J.
Liu, and X.
Cao, Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review.
Journal of autoimmunity, 2017.
83: p.
1-11.
9.
Chou, W.
-C.
, et al.
, AIM2 in regulatory T cells Restrains autoimmune diseases.
Nature, 2021: p.
1-6.
Reprinting [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author owns all legal rights.
Offenders must be investigated.
.
1480-1483.
7.
Ascherio, A.
and KL Munger, Epstein–Barr virus infection and multiple sclerosis: a review.
Journal of Neuroimmune Pharmacology, 2010.
5(3): p.
271-277.
8.
Chen, K.
, J.
Liu , and X.
Cao, Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review.
Journal of autoimmunity, 2017.
83: p.
1-11.
9.
Chou, W.
-C.
, et al.
, AIM2 in regulatory T cells restrains autoimmune diseases.
Nature, 2021: p.
1-6.
Reprinting [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators Must be investigated.
1480-1483.
7.
Ascherio, A.
and KL Munger, Epstein–Barr virus infection and multiple sclerosis: a review.
Journal of Neuroimmune Pharmacology, 2010.
5(3): p.
271-277.
8.
Chen, K.
, J.
Liu , and X.
Cao, Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review.
Journal of autoimmunity, 2017.
83: p.
1-11.
9.
Chou, W.
-C.
, et al.
, AIM2 in regulatory T cells restrains autoimmune diseases.
Nature, 2021: p.
1-6.
Reprinting [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators Must be investigated.
AIM2 in regulatory T cells restrains autoimmune diseases.
Nature, 2021: p.
1-6.
Reprinting information [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights , The offender must be investigated.
AIM2 in regulatory T cells restrains autoimmune diseases.
Nature, 2021: p.
1-6.
Reprinting information [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights , The offender must be investigated.