ACS DIVISION OF BIOLOGICAL CHEMISTRY

March 19th, 2015 by Chernov, A. V., Dolkas, J., Hoang, K., Angert, M., Srikrishna, G., Vogl, T., Baranovskaya, S., Strongin, A. Y., Shubayev, V. I.

To shed light on the early immune response processes in severed peripheral nerve, we performed genome-wide transcriptional profiling and bioinformatics analyses of the proximal (P; regenerating) and distal (D; degenerating) nerve stumps at day 1 in the sciatic nerve axotomy model in rats. Multiple cell death-related pathways were activated in the degenerating D stump, whereas activation of the cytoskeletal motility and gluconeogenesis/glycolysis pathways was most prominent in the P stump of the axotomized nerve. Our bioinformatics analyses also identified the specific immunomodulatory genes of the chemokine, interleukin (IL), tumor necrosis factor (TNF), major histocompatibility complex (MHC), immunoglobulin-binding Fc receptor, calcium-binding S100, matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and ion channel families affected in both the P and D segments. S100a8 and S100a9 were the top up-regulated genes in both the P and D segments. Stimulation of cultured Schwann cells using the purified S100A8/A9 heterodimer recapitulated activation of the myeloid cell and phagocyte chemotactic genes and pathways, which we initially observed in injured nerve. The S100A8/A9 heterodimer injection into the intact nerve stimulated macrophage infiltration. We conclude that following peripheral nerve injury an immediate acute immune response occurs both distally and proximally to the lesion site and that the rapid transcriptional activation of the S100a8/S100a9 genes results in the S100A8/A9 hetero and homodimers, which stimulate the release of chemokines and cytokines by the activated Schwann cells and generate the initial chemotactic gradient that guides transmigration of hematogenous immune cells into the injured nerve.