Identification of a new functional domain of Nogo‐A that promotes inflammatory pain and inhibits neurite growth through binding to NgR1

Abstract

Nogo-A is a key inhibitory molecule to axon regeneration, and plays diverse roles in other pathological conditions, such as stroke, schizophrenia, and neurodegenerative diseases. Nogo-66 and Nogo-Δ20 fragments are two known functional domains of Nogo-A, which act through the Nogo-66 receptor (NgR1) and sphingosine-1phosphate receptor 2 (S1PR2), respectively. Here, we reported a new functional domain of Nogo-A, Nogo-A aa 846-861, was identified in the Nogo-A-specific segment that promotes complete Freund's adjuvant (CFA)-induced inflammatory pain. Intrathecal injection of its antagonist peptide 846-861PE or the specific antibody attenuated the CFA-induced inflammatory heat hyperalgesia. The 846-861 PE reduced the content of transient receptor potential vanilloid subfamily member 1 (TRPV1) in dorsal root ganglia (DRG) and decreased the response of DRG neurons to capsaicin. These effects were accompanied by a reduction in LIMK/cofilin phosphorylation and actin polymerization. GST pull-down and fluorescence resonance energy transfer (FRET) assays both showed that Nogo-A aa 846-861 bound to NgR1. Moreover, we demonstrated that Nogo-A aa 846-861 inhibited neurite outgrowth from cortical neurons and DRG explants. We concluded that Nogo-A aa 846-861 is a novel ligand of NgR1, which activates the downstream signaling pathways that inhibit axon growth and promote inflammatory pain.

Mechanism of action of Shaoyao-Gancao decoction in relieving chronic inflammatory pain via Sema3G protein regulation in the dorsal root ganglion

“…Numerous studies have found that CIP can lead to changes in the expression of both proteins and cytokines in the DRG. Liu et al [ 30 , 31 ] found that the Nogo-A protein was significantly increased in the DRG of rats with CIP. The expression levels of CCL2 and its receptor (CCR2) in the DRG were significantly increased in CIP model rats, and CCL2 improved the excitability of nociceptive cells in the DRG.…”

Effects of exercise training on neurological recovery, TGF-β1, HIF-1α, and Nogo-NgR signaling pathways after spinal cord injury in rats

“… 18 Nogo-A is Nogo gene's full-length expression and possesses the structural-functional domains Nogo-A-20 and Nogo-A-66, both of which can stabilize the outer fiber skeleton of neurons and prevent cell adhesion and migration by activating the Rho/ROCK pathway and raising Ca2+ levels. 19 This further causes growth cone collapse and inhibits CNS axons. 20 NgR is a receptor for Nogo protein inhibition, and the family includes NgR1, NgR2, and NgR3, among which NgR1 needs to bind to the low-affinity neurotrophic factor receptor p75 or TROY or the nervous system-specific transmembrane protein LINGO-1 to co-mediate the myelin inhibitory response because it cannot mediate transmembrane or intracellular signaling.…”

The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches

“…Moreover, Nogo receptors (NgR1 and NgR2) located on the cell surface participate in the migration of macrophages from inflammation sites in the peripheral nerve [ 60 ]. Not only does Nogo-A promote the activation of the inflammatory process mediated by the release of pro-inflammatory cytokines, but it is also a crucial factor regulating the perception of pain associated with inflammation in dorsal root ganglion (DRG) neurons [ 29 , 30 ]. Nogo-A aa 846–861 is a Nogo-A-specific segment and a novel ligand of NgR1 which promotes inflammatory pain [ 30 ].…”

“…Not only does Nogo-A promote the activation of the inflammatory process mediated by the release of pro-inflammatory cytokines, but it is also a crucial factor regulating the perception of pain associated with inflammation in dorsal root ganglion (DRG) neurons [ 29 , 30 ]. Nogo-A aa 846–861 is a Nogo-A-specific segment and a novel ligand of NgR1 which promotes inflammatory pain [ 30 ]. Nogo-A regulates inflammatory heat hyperalgesia by suppressing the transient receptor potential vanilloid subfamily member (TRPV)-1 channel, the endogenous noxious heat transducer during inflammation, and activation of the LIM domain kinase (LIMK)/cofilin signalling pathway.…”