Setter, Deborah Olmstead;
Runge, Elizabeth M;
Schartz, Nicole D;
Sanders, Virginia M;
Jones, Kathryn J
Gene expression profile analysis of immunodeficient mice after WT or mSOD1 immunoreconsitution reveals differential motoneuron death mechanisms after facial nerve axotomy
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Medientyp:
E-Artikel
Titel:
Gene expression profile analysis of immunodeficient mice after WT or mSOD1 immunoreconsitution reveals differential motoneuron death mechanisms after facial nerve axotomy
Beteiligte:
Setter, Deborah Olmstead;
Runge, Elizabeth M;
Schartz, Nicole D;
Sanders, Virginia M;
Jones, Kathryn J
Beschreibung:
<jats:p>When a facial nerve axotomy (FNA) is performed on recombinase activating gene‐2 knockout (RAG‐2<jats:sup>−/−</jats:sup>) mice lacking the adaptive arm of the immune system, there is significantly greater motoneuron (MN) death relative to wild type (WT) mice. Reconstituting RAG‐2<jats:sup>−/−</jats:sup> mice with whole splenocytes (WS) restores MN survival to WT levels, and CD4+ T cells specifically were found to drive immune‐mediated neuroprotection. The mSOD1 mouse model of amyotrophic lateral sclerosis (ALS), a MN disease, also exhibits significantly decreased MN survival after FNA, and this model mimics the immune dysregulation described in human ALS patients. Reconstituting RAG‐2<jats:sup>−/−</jats:sup> mice with mSOD1 WS fails to rescue MN survival, whereas isolated mSOD1 CD4+ T cell reconstitution confers neuroprotection. This finding suggests an inhibitory factor in mSOD1 mice blocks CD4+ T cell‐mediated neuroprotection. The <jats:italic>objective</jats:italic> of the current study is to characterize the mechanisms of neuroprotection in a wild‐type immune system and then identify disruptions of these processes in the mSOD1 mouse model of ALS.</jats:p><jats:p>To accomplish this goal, gene expression profiles of the axotomized facial motor nucleus were gathered from 6 experimental groups: WT, RAG‐2<jats:sup>−/−</jats:sup>, RAG‐2<jats:sup>−/−</jats:sup> + WT WS, RAG‐2<jats:sup>−/−</jats:sup> + WT CD4+ T cells, RAG‐2<jats:sup>−/−</jats:sup> + mSOD1 WS, and RAG‐2<jats:sup>−/−</jats:sup> + mSOD1 CD4+ T cells. Genes associated with MN regeneration, glial activation, inflammatory cytokines, and cell death pathways were examined. Our findings revealed that relative to WT mice, MN regeneration and cell death pathways were unaffected in RAG‐2<jats:sup>−/−</jats:sup> mice, but glial activation and cytokine expression were significantly reduced. Adoptive transfer of WT or mSOD1 WS or CD4+ T cells into RAG‐2<jats:sup>−/−</jats:sup> mice restored glial activation and cytokine production to WT levels. MN‐specific Fas cell death receptor expression, which is increased in mSOD1 mice after FNA, is also elevated in RAG‐2<jats:sup>−/−</jats:sup> + mSOD1 WS mice. These data implicate a dysregulated glial response as a causative factor for MN death in immunodeficient mice. In contrast, promotion of the Fas/Fas ligand pathway may contribute to MN death in immunodeficient mice reconstituted with mSOD1 WS. In summary, these results suggest that peripheral immune cells can directly modulate central responses to injury. Future studies based upon these results are expected to elucidate how mSOD1 immune cells promote Fas expression, and whether inhibition of the process can preserve MN.</jats:p><jats:p><jats:bold>Support or Funding Information</jats:bold></jats:p><jats:p>Supported by NIH NS40433 (KJJ and VMS)</jats:p>