The alternatively spliced fibronectin CS1 isoform regulates IL-17A levels and mechanical allodynia after peripheral nerve injury

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/aα4 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. © 2015 liu et al.