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 7

NLRP3 regulates ASC aggregation and distribution following CHI.

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NLRP3 regulates ASC aggregation and distribution following CHI. (A) IHC ...
(A) IHC images for Iba1 (green), GFAP (magenta), and ASC (red) staining in cortices of WT and Nlrp3–/– mice at 7 and 21 dpi. ASC localization in Iba1+ cells (yellow spots), GFAP+ cells (blue spots), and outside glial cells (red spots) was analyzed using IMARIS. Rectangles highlight examples of ASC distribution in high-magnification views. Scale bars: 20 μm. (B–E) Quantification of total ASC aggregates (B), intracellular ASC aggregates in Iba1+ cells (C), ASC aggregates outside glial cells (D), and ASC aggregates with a volume range of 30–40 μm3 (E) at 7 and 21 dpi in WT and Nlrp3–/– mice subjected to sham surgery or CHI. n = 12 slices from 4 mice per group per time point. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by ordinary 2-way ANOVA with Bonferroni’s post hoc test (B–E, left panels) and 2-tailed Student’s t test (B–E, right panels). Right panels show integrative AUC of each marker over time (dpi). Data are presented as the mean ± SEM. (F–I) Spearman’s correlation analysis (r) with a linear regression model (black lines represent WT mice; red lines represent Nlrp3–/– mice) with an interaction term for ASC aggregates (total, within glial cells and outside glial cells) and glial cell contact areas. n = 36 slices from 12 mice per genotype. ****P < 0.0001. Differences between WT and Nlrp3–/– Spearman correlation coefficients (r) were calculated using standard Fisher’s z-transformation and subsequent comparison (87). *P < 0.05 and **P < 0.01.