# Autonomic Regulation of the Immunological Response to Limb Injury

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2023 · —

## Abstract

A major recent advancement for the field of pain research is the recognition of immune system
dysregulation as a contributor to the most serious adverse outcomes from injury. Both autoinflammation
involving mediators of inflammation and autoimmunity involving autoantibodies have been identified in
patients with chronic pain and disability after limb trauma. Taking advantage of these advancements, the
overarching goal of the proposed research is to identify novel approaches to controlling immune system
activation after limb injury thereby increasing the rate and improving the quality of recovery while reducing
chronic pain, functional loss and neuropsychiatric consequences such as anxiety and cognitive decline.
Building on evidence from the fields of immunology, pain and rehabilitation, this project will focus on the
autonomic regulation of the immune system after injury. The proposed experiments involve a well-validated
rodent tibial fracture model of limb injury as well as samples obtained from patients with chronic limb pain
after traumatic events. Our central hypothesis is that interruption of a sympathetically-initiated
immunological cascade will greatly enhance the rate and quality of recovery by reducing IL-6 production,
autoantibody formation and activation of the complement cascade.
 The project is divided into three aims. In the first aim we will determine whether modulation of autonomic
outflow after tibial fracture reduces immune activation and improves key dimensions of recovery. We
hypothesize that post-traumatic activation of the sympathetic nervous system sets an immunological
pathway in motion including IL-6 expression, IgM autoantibody production and complement activation
ultimately leading to chronic pain, functional decline, anxiety and cognitive decline. Activation of the
parasympathetic nervous system may have opposite effects. Using neuroablative and pharmacological
approaches, we will test this hypothesis using a panel of outcome measures designed to address multiple
dimensions of recovery.
 In the project’s second aim we focus strongly on the roles of IL-6 signaling after limb injury as a mediator
supporting IgM autoantibody production. We hypothesize that blocking the sympathetically-enhanced
production of IL-6 after limb injury will reduce autoantigen expression in the injured limbs, regional lymph
node hypertrophy, B-cell differentiation and IgM autoantibody production. We will use genetic tools as well
as clinically available biologic and small molecule anti-IL-6 agents to define the role of this cytokine in
supporting the long-term adverse outcomes of limb injury.
 Finally, the project’s third aim is to determine whether injury-related autoantibodies support adverse
outcomes via peripheral and central complement system activation. We hypothesize that IgM
autoantibodies produced by limb injured mice and, translationally, limb injured patients support complement
cascade activation leading to the generation of pain-promo...

## Key facts

- **NIH application ID:** 10642809
- **Project number:** 5I01RX001475-09
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** DAVID J. CLARK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10642809

## Citation

> US National Institutes of Health, RePORTER application 10642809, Autonomic Regulation of the Immunological Response to Limb Injury (5I01RX001475-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10642809. Licensed CC0.

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