Indiana University-Purdue University Indianapolis (IUPUI) / Facial nerve axotomy (FNA) in immunodeficient mice causes significantly more
facial motoneuron (FMN) loss relative to wild type (WT), indicating that the immune
system is neuroprotective. Further studies reveal that both CD4+ T cells and interleukin
10 (IL-10) act centrally to promote neuronal survival after injury. This study first
investigated the roles of IL-10 and CD4+ T cells in neuroprotection after axotomy.
CD4+ T cell-mediated neuroprotection requires centrally-produced IL-10, but the
source of IL-10 is unknown. Using FNA on IL-10 reporter mice, immunohistochemistry
was employed to identify the IL-10 source. Unexpectedly, axotomy induced astrocyte
production of IL-10. To test if microglia- or astrocyte-specific IL-10 is needed for
neuroprotection, cell-specific conditional knockout mice were generated. Neither
knockout scenario affected FMN survival after FNA, suggesting that coordinated IL-10
production by both glia contributes to neuroprotection.
The effect of immune status on the post-FNA molecular response was studied to
characterize CD4+ T cell-mediated neuroprotection. In the recombinase-activating gene2 knockout (RAG-2-/-) mouse model of immunodeficiency, glial microenvironment
responses were significantly impaired. Reconstitution with CD4+ T cells restored glial
activation to normal levels. Motoneuron regeneration responses remained unaffected by
immune status. These findings indicate that CD4+ T cell-mediated neuroprotection after
injury occurs indirectly via microenvironment regulation. Immunodysregulation is evident in amyotrophic lateral sclerosis (ALS), and FMN
survival after FNA is worse in the mutant superoxide dismutase (mSOD1) mouse model
of ALS. Further experiments reveal that mSOD1 CD4+ T cells are neuroprotective in RAG-2-/- mice, whereas mSOD1 whole splenocytes (WS) are not. The third aim
examined if the mSOD1 WS environment inhibits mSOD1 CD4+ T cell glial regulation
after axotomy. Unexpectedly, both treatments were equally effective in promoting glial
activation. Instead, mSOD1 WS treatment induced a motoneuron-specific death
mechanism prevalent in ALS.
In conclusion, the peripheral immune system regulates the central glial
microenvironment utilizing IL-10 to promote neuronal survival after axotomy.
Astrocytes, specifically, may be responsible for transducing peripheral immune signals
into microenvironment regulation. Additionally, the immune system in ALS may directly
participate in disease pathology.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/12537 |
| Date | 08 March 2017 |
| Creators | Setter, Deborah Olmstead |
| Contributors | Jones, Kathryn J., Block, Michelle L., Sanders, Virginia M., Sengelaub, Dale R., Xu, Xiao-Ming |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
Page generated in 0.0019 seconds