Inactivity‐induced phrenic motor facilitation is initiated though TNF receptor 2 and impaired by TNF receptor 1
Abstract
Prolonged reductions in synaptic inputs to phrenic motor neurons results in the release of spinal, soluble TNFα (sTNFα) to initiate a long lasting increase in phrenic burst amplitude termed inactivity‐induced phrenic motor facilitation (iPMF). TNFα can activate TNF‐R1 or TNF‐R2, which are two distinct cell surface receptors that tend to initiate discrete signaling cascades. TNF‐R1 mediates the majority of TNFα activity; therefore, we hypothesized sTNFα released within or near the phrenic motor pool in response to reduced activity binds to TNF‐R1 on phrenic motor neurons to initiate iPMF. To test this hypothesis, Harlan Sprague Dawley rats were injected with small interfering RNAs directed against TNF‐R1 or TNF‐R2 in the interpleural space (100pg/side) to selectively reduce TNF‐R1 or TNF‐R2 in phrenic motor neurons. After 3 daily injections of siRNAs, iPMF was measured in anesthetized and ventilated rats for 60min following a prolonged (30min) neural apnea. As expected, control rats receiving injections of non‐targeting siRNA expressed an increase in phrenic burst amplitude for up to 60min following neural apnea (48±15,%baseline), indicating iPMF. Contrary to our hypothesis, knockdown of TNF‐R1 in phrenic motor neurons led to an enhanced iPMF following prolonged neural apnea (80±18,%baseline), whereas knockdown of TNF‐R2 completely abolished the expression of iPMF 60min post neural apnea (−8±5,%baseline,). Collectively, these data suggest that TNF‐R2 signaling in phrenic motor neurons is necessary for iPMF and that TNF‐R1 signaling may initiate mechanisms within phrenic motor neurons that oppose iPMF. Thus, both TNFα receptors may contribute to sculpting phrenic burst amplitude in response to a reduction in respiratory‐related neural inputs.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2016
- Source ID
- 10.1096/fasebj.30.1_supplement.1294.4
Entities
People
- Abiye Agbeh
- Kendra Braegelmann
- Stephanie Fischer
- Tracy Baker
Organizations
- United States Department of Defense
- University of Wisconsin–Madison