The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury
Authors: Veronica I Shubayev
Khan Hoang
Mila Angert
Huaqing Liu
Tasuku Nishihara
Alex Y Strongin
Andrei V Chernov
Sergey A Shiryaev
Jennifer Dolkas
Albert G Remacle
Journal: Journal of Neuroinflammation (2015)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Mechanical pain hypersensitivity; T-helper cells; interleukin-17A; Fibronectin; CS1
Affiliations: Department of Anesthesiology, University of California, 9500 Gilman Dr., Mail Code 0629, La Jolla, San Diego, CA, 92093-0629, USA. ., VA San Diego Healthcare System, La Jolla, CA, USA. ., Sanford-Burnham Medical Research Institute, La Jolla, CA, USA. .

Abstract:  Background: Mechanical pain hypersensitivity associated with physical trauma to peripheral nerve depends on T-helper (Th) cells expressing the algesic cytokine, interleukin (IL)-17A. Fibronectin (FN) isoform alternatively spliced within the IIICS region encoding the 25-residue-long connecting segment 1 (CS1) regulates T cell recruitment to the sites of inflammation. Herein, we analyzed the role of CS1-containing FN (FN-CS1) in IL-17A expression and pain after peripheral nerve damage. Methods: Mass spectrometry, immunoblotting, and FN-CS1-specific immunofluorescence analyses were employed to examine FN expression after chronic constriction injury (CCI) in rat sciatic nerves. The acute intra-sciatic nerve injection of the synthetic CS1 peptide (a competitive inhibitor of the FN-CS1/Œ±4 integrin binding) was used to elucidate the functional significance of FN-CS1 in mechanical and thermal pain hypersensitivity and IL-17A expression (by quantitative Taqman RT-PCR) after CCI. The CS1 peptide effects were analyzed in cultured primary Schwann cells, the major source of FN-CS1 in CCI nerves. Results: Following CCI, FN expression in sciatic nerve increased with the dominant FN-CS1 deposition in endothelial cells, Schwann cells, and macrophages. Acute CS1 therapy attenuated mechanical allodynia (pain from innocuous stimulation) but not thermal hyperalgesia and reduced the levels of IL-17A expression in the injured nerve. CS1 peptide inhibited the LPS- or starvation-stimulated activation of the stress ERK/MAPK pathway in cultured Schwann cells. Conclusions: After physical trauma to the peripheral nerve, FN-CS1 contributes to mechanical pain hypersensitivity by increasing the number of IL-17A-expressing (presumably, Th17) cells. CS1 peptide therapy can be developed for pharmacological control of neuropathic pain. 

Retracted: No

PubPeer comments:
 Readers should become aware of a recent preprint entitled  FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau fibers , which argues that  that the interpretation of the FRET-effect is not tenable, because the TauRD-GFP in the sensor cells cannot assemble into PHF-like fibers upon adopting some misfolded Tau conformation transmitted from outside the cell. As such, this also invalidates the underlying assumption that only some extracellular misfolded tau could be the carrier of pathogenic information. From the abstract:  Using biophysical methods (light scattering, atomic force microscopy (AFM), and scanning-transmission electron microscopy (STEM)), we found that the assembly of TauRDu0394K-GFP was severely inhibited, even in the presence of nucleation enhancers (heparin and or pre-formed PHFs from TauRDu0394K). Some rare fiber-like particles had a very different subunit packing from proper PHFs, as judged by STEM. The mass per length (MPL) values of TauRDu0394K fibrils are equivalent to 4.45 molecules nm, close to the expected value for a paired-helical fiber with 2 protofilaments and cross-u03b2 structure. By contrast, the elongated particles formed by TauRDu0394K-GFP have MPL values around u223c2, less than half of the values expected for PHFs, indicating that the subunit packing is distinct. **Thus, both kinetic and structural observations are incompatible with a model whereby external Tau can form a template for PHF assembly of Tau-GFP in recipient cells. As a consequence, the observed local increase of FRET in recipient cells must be caused by other signalling processes** ,