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Sympathetic nerve repulsion inhibited by designer molecules in vitro and role in experimental arthritis

: Kunath, Julia; Delaroque, Nicolas; Szardenings, Michael; Neundorf, Ines; Straub, Rainer H.


Life sciences 168 (2017), pp.47-53
ISSN: 0024-3205
ISSN: 1879-0631
Deutsche Forschungsgemeinschaft DFG
STR 511/23-1
Journal Article
Fraunhofer IZI ()
sympathetic nerve fiber; inflammation; Arthritis; nerve fiber repulsion; nerve repellent factors

Aims: In rheumatoid arthritis and collagen type II arthritis (CIA), sympathetic nerve fibers get lost in inflamed tissue. The process is probably induced by nerve repellent factors like semaphorin 3F (SEMA3F). Repulsion of sympathetic nerve fibers in inflamed tissue has proinflammatory effects dueto the loss of anti-inflammatory neurotransmitters. We hypothesized thatdesign molecules like antibodies and specific peptides that inhibit nerve fiber repulsion can ameliorate CIA.
Materials and methods: Two blocking antibodies were used and four blocking peptides were generated using the phage display technique with the targets of SEMA3F and plexin-A2. All blocking molecules were tested in vitro using a sympathetic neurite outgrowth assay. CIA was induced by collagen type II in mice.
Key findings: In the neurite outgrowth assay, the two antibodies against plexin-A2 and neuropilin-2 as well as the four blocking peptides – two SEMA3F analogouspeptides (WLFQRDPGDR, QATVKWLFQRDPGDRR) and two plexin A2 analogous peptides (DSSDQFSFDYELEQN, DSSIQFFSFEKDKERI) - were able to block sympathetic nerve fiber repulsion in vitro (at 150–600 nmol/l). Administration of the two antibodies prophylactically on day 4 after immunization did not change clinical CIA. Similarly, using the top candidate antibody to plexin-A2 after CIA onset (mild score of 4 points, maximum = 52 points), did not ameliorate CIA. The testedblocking peptides were not recovered in peripheral blood after i.v. andi.p. administration.
Significance: While designer molecules blocked nerve fiber repulsion in vitro, therapeutic administration in vivo did not change CIA.Possible strategies to overcome negative effects demonstratedin vivo are discussed.