Changes in microglial proliferation rate in GFAP-IL10Tg mice following perforant pathway transection

Abstract

Activation and proliferation of microglia are key events in the response of CNS against inflammatory diseases. Cytokines play an important role in the control of these processes. Although production of interleukin-10 (IL-10) by activated astrocytes and microglia has been demonstrated after different CNS injuries, the specific role played by IL-10 in modulating microglial proliferation remains unclear. Hence, the objective of this study was to evaluate the effects of local IL-10 production on microglial proliferation in normal conditions and associated with axonal anterograde degeneration. For this purpose, unilateral perforant pathway transection (PPT) was performed in transgenic mice with astrocyte-targeted production of IL-10 (GFAP-IL10Tg) and their corresponding wild type (WT) littermates. At 2, 3 and 7 days post-lesion (dpl), animals were intracardially perfused with 4% of paraformaldehyde and brains processed for immunohistochemical studies. Microglial cell number was quantified using the myeloid-specific transcription factor PU.1 and microglial proliferation was evaluated using the mitotic marker Phospho Histone H3 (pH3). Our results showed a significant increase in the number of microglial cells in GFAP-IL10Tg mice compared with WT, in both non-lesioned and lesioned animals. The peak of proliferation after PPT lesion was delayed in GFAP-IL10Tg mice showing the maximum number of pH3+ cells at 3dpl, while in WT the peak was observed at 2dpl. Moreover, the number of proliferating cells was lower in Tg mice at the different time points analyzed. In conclusion, this study demonstrated that local production of IL-10 in the CNS modifies the microglial proliferation pattern associated with PPT. Further studies are necessary to understand the mechanisms involved in microglial proliferation in this paradigm. Supported by Ministerio de Ciencia e Innovacion (BFU2011-27400).