Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model
Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka
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Research Article Inflammation Neuroscience

Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model

Abstract

Mild traumatic brain injury (mTBI) from a closed-head injury (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI (mCHI) is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA-seq analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation, and astrocyte reactivity persisted up to 21 days in a model for mTBI, with significant reduction of this pattern in Asc–/– mice. Importantly, mild cognitive impairment induced after mCHI was largely abrogated in Asc–/– mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mCHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.

Authors

Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Gou, Valentin Stein, Douglas T. Golenbock, Eicke Latz, Michael T. Heneka

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Figure 3

Morphology of Iba1+ and GFAP+ cells is modulated by ASC following CHI.

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Morphology of Iba1+ and GFAP+ cells is modulated by ASC following CHI. (...
(A) IHC images of Iba1 (green, presumably microglia) staining in cortices from WT and Asc–/– mice subjected to sham surgery or at 1, 7, and 21 dpi. Arrows indicate representative morphological changes. Scale bar: 20 μm. (B) Representative skeletonized Iba1+ cells following CHI. Scale bars: 10 μm. Quantitative analysis of (C) Iba1+ cell counts, (D) branch numbers per cell, (E) total branch length per cell, and (F) endpoint numbers per cell at 1, 7, and 21 dpi for WT and Asc–/– mice subjected to sham or CHI. (G) IHC images of GFAP (magenta, presumably astrocytes) in cortices from WT and Asc–/– mice at 1, 7, and 21 dpi. Arrows indicate representative morphological changes. Scale bar: 20 μm. (H) Representative skeletonized GFAP+ cells following CHI. Scale bars: 10 μm. Quantitative analysis of (I) GFAP+ cell counts (J) branch numbers per cell, (K) total branch length per cell, and (L) endpoint numbers per cell at 1, 7, and 21 dpi for WT and Asc–/– mice subjected to sham surgery or CHI. n = 12 slices from 4 mice per group per time point. **P < 0.01 and ***P < 0.001, by ordinary 2-way ANOVA with Bonferroni’s post hoc test and 2-tailed Student’s t test. 27. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by ordinary 2-way ANOVA with Bonferroni’s test (C–F and I–L, left panels) and Student’s t test (C–F and I–L, right panels). Data are presented as the mean ± SEM. Right panels show the integrative AUC of each marker over time (dpi).