The AIM2 inflammasome is activated in astrocytes during the late phase of EAE
William E. Barclay, Nupur Aggarwal, M. Elizabeth Deerhake, Makoto Inoue, Toshiaki Nonaka, Kengo Nozaki, Nathan A. Luzum, Edward A. Miao, Mari L. Shinohara
William E. Barclay, Nupur Aggarwal, M. Elizabeth Deerhake, Makoto Inoue, Toshiaki Nonaka, Kengo Nozaki, Nathan A. Luzum, Edward A. Miao, Mari L. Shinohara
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Resource and Technical Advance Neuroscience

The AIM2 inflammasome is activated in astrocytes during the late phase of EAE

Abstract

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 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 used multiple genetically modified mouse models to monitor activated inflammasomes in situ based on oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) 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 during EAE was dependent on absent in melanoma 2 (AIM2), but low IL-1β release and no significant signs of cell death were found. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.

Authors

William E. Barclay, Nupur Aggarwal, M. Elizabeth Deerhake, Makoto Inoue, Toshiaki Nonaka, Kengo Nozaki, Nathan A. Luzum, Edward A. Miao, Mari L. Shinohara

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Figure 2

No inflammasome activation in hematopoietic cells in the CNS during EAE.

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No inflammasome activation in hematopoietic cells in the CNS during EAE....
(A) EAE disease scores of WT (BM donor)→WT (recipient) chimeras versus WT→Pycard–/– chimeras. n = 7, combined from multiple experiments. Each data point represents a mean value among a group. (B and C) Comparison of EAE disease severity of WT→WT chimeras versus WT→Pycard–/– chimeras. Each data point represents a value from 1 mouse (n = 7), combined from multiple experiments. AUC quantification of prepeak disease (B), AUC quantification of postpeak disease (C). (D–F) Representative images (D and E) and quantification (F) of ASC specks in the iLNs of ASC-Citrine→WT chimeras (D) versus WT→ASC-Citrine chimeras (E) at 3 dpi of EAE. Each data point represents a value from 1 mouse as an average of both iLNs (n = 4). Mann-Whitney U test was used. Scale bar is 20 μm. (G–J) Representative images (G and H) and quantification of ASC specks (I) and ASC strings (J) of SC from WT→ASC-Citrine BM chimeras (n = 4) versus ASC-Citrine→WT chimeras (n = 6) at 30 dpi of EAE. Each data point represents a value from 1 mouse. Mann-Whitney test was used (B, C, F, I, and J). Scale bar is 300 μm. *P < 0.05, **P < 0.01, ***P < 0.001. Error bars denote mean ± SEM (A–C, F, I, and J).