title: The calcium-binding proteins S100A8 and S100A9 initiate the early inflammatory program in injured peripheral nerves.
abstract: To shed light on the early immune response processes in severed peripheral nerves, we performed genome-wide transcriptional profiling and bioinformatics analyses of the proximal (P, regenerating) and distal (D, degenerating) nerve stumps on 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, IL, TNF, MHC, immunoglobulin-binding Fc receptor, calcium-binding S100, matrix metalloproteinase, tissue inhibitor of metalloproteinase, 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 nerves. 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 distal and proximal to the lesion site and that the rapid transcriptional activation of the S100a8 and S100a9 genes results in S100A8/A9 hetero- and homodimers, which stimulate the release of chemokines and cytokines by activated Schwann cells and generate the initial chemotactic gradient that guides the transmigration of hematogenous immune cells into the injured nerve.
authors: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors: Andrei V
authors: AV
authors: Chernov
authors: the Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, the Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors: Jennifer
authors: J
authors: Dolkas
authors: the Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, the Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors: Khang
authors: K
authors: Hoang
authors: the Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, the Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors: Mila
authors: M
authors: Angert
authors: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors: Geetha
authors: G
authors: Srikrishna
authors: the Institute of Immunology, University of Münster, D-48149 Münster, Germany, and.
authors: Thomas
authors: T
authors: Vogl
authors: Agilent Technologies, La Jolla, California 92037.
authors: Svetlana
authors: S
authors: Baranovskaya
authors: From the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors: Alex Y
authors: AY
authors: Strongin
authors: the Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, the Veterans Affairs San Diego Healthcare System, La Jolla, California 92037, vshubayev@ucsd.edu.
authors: Veronica I
authors: VI
authors: Shubayev
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects* / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D018925:Chemokines; D011494:Protein Kinases
keywords: Cellular Immune Response; Chemokine; Cytokine; Gene Expression; Nerve Regeneration; Peripheral Nerve; S100 Proteins; Schwann Cells