# Inflammasome activation and lymphatic dysfunction in traumatic brain injury

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $353,281

## Abstract

ABSTRACT
Traumatic brain injury (TBI) affects millions of people worldwide every year and current estimates from the
World Health Organization suggest that TBI will be the third leading cause of death and disability by the year
2020. Despite being a prevalent and pressing global medical issue, our understanding of TBI pathoetiology
remains incomplete. Proper drainage of cellular debris by the lymphatic system is required to maintain tissue
homeostasis and impaired removal of damage/stress signals, including damaged cells and protein aggregates,
from organs has been linked to a spectrum of diseases. In comparison to other peripheral organs, our
understanding of how our how defects in lymphatic drainage from the central nervous system (CNS) contribute
to disease remains poorly described. In this project, we will investigate the consequences of compromised
meningeal lymphatic function in TBI pathogenesis. In our preliminary studies, we found that TBI results in
severely compromised brain lymphatic drainage and that pre-existing deficits in meningeal lymphatic function
predisposes the brain to exacerbated clinical disease following brain trauma. To determine if the impaired
clearance of endogenous damage/stress signals (e.g., cellular debris and necrotic cells) was associated with
inflammatory signaling, we evaluated inflammasome complex formation in TBI. Inflammasomes are
multiprotein oligomeric platforms that coordinate IL-1 and IL-18 production, as well as an inflammatory form of
cell death in response to damage/stress signals. We find that injury-induced meningeal lymphatic dysfunction
is associated with pronounced inflammasome formation and accumulation in the TBI brain. Moreover, our
preliminary findings and work from others demonstrate critical roles for inflammasome activation in TBI disease
pathogenesis. Given these collective findings, we hypothesize that aberrant inflammasome signaling that
results from meningeal lymphatic dysfunction mechanistically contributes to TBI pathogenesis. To test this, we
propose three aims. In Aim 1, we will employ a series of cutting-edge meningeal lymphatic modifying
approaches to identify how modulation of brain drainage influences TBI disease progression. In Aim 2, will
determine to what extent inflammasome signaling downstream of meningeal lymphatic dysfunction
mechanistically contributes to TBI pathology. In the third Aim, we will investigate how CNS lymphatic decline
that occurs with aging influences TBI disease outcomes in the elderly. This research is innovative because it
will break new ground in our understanding of how disruptions in brain drainage and the resulting buildup of
inflammasome oligomers influence CNS disease progression. Moreover, our preliminary studies suggest that
modulation of the meningeal lymphatics and inflammasome signaling can potentially serve as much-needed
therapeutic strategies to treat TBI, which further underscores the translational value of these studies.

## Key facts

- **NIH application ID:** 10222790
- **Project number:** 5R01NS106383-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** John R Lukens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,281
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222790

## Citation

> US National Institutes of Health, RePORTER application 10222790, Inflammasome activation and lymphatic dysfunction in traumatic brain injury (5R01NS106383-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10222790. Licensed CC0.

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