The ion channel TRPA1 is required for suppression of inflammation

Project Summary/Abstract
Inflammation, the essential biological response to infection and injury, is tightly controlled by the nervous system.
Inflammatory cytokines and other mediators produced by immune cells during infection and injury activate
sensory action potentials in the vagus nerve. The arrival of these incoming signals stimulates brain neural circuits
to initiate a reflex response that return to the body and regulate cytokine production. We recently identified a
critical role for the transient receptor potential ankyrin-1 (TRPA1) in mediating interleukin-1β-specific biological
responses. Sensory signals transmitted via vagus TRPA1-stimulation inhibit endotoxin-induced cytokine storm
and significantly reduce the lethality of bacterial sepsis. Despite the direct evidence of vagus TRPA1-mediated
afferent signaling, almost nothing is known about the brain neural networks activated by vagus TRPA1 signaling
and regulating inflammation. Our long-term goal is to reveal neural circuits regulating the onset and progression
of inflammation. These discoveries will facilitate the design of novel therapeutic strategies targeting neural
circuits for the treatment of inflammatory conditions. The objective of this grant is to provide mechanistic insight
into the brain neural networks that regulate inflammatory changes. The central hypothesis is that vagus TRPA1-
elicited brain neural networks play a critical role in regulating inflammation. Here, we will leverage powerful
genetic, bioelectronic and chemogenetic approaches for functional mapping to define brain neural networks
activated by vagus TRPA1-signaling, and how they relay outputs to the vagus nerve to impact inflammatory
responses. In Specific Aim 1, we will use genetic techniques to “label” subsets of neurons selectively activated
by vagus sensory signals. In Specific Aim 2, we will use viral vectors and chemogenetic tools to selectively
modulate these brain networks to assess its impact on inflammation and vagus nerve signaling. Upon conclusion,
the proposed studies will establish the mechanistic understanding of TRPA1-elicited brain neural networks that
can be targeted by several available brain stimulating modalities using invasive and noninvasive technologies to
regulate inflammation.
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Grant Number: 2R01GM132672-05
NIH Institute/Center: NIH
Principal Investigator: Sangeeta Chavan