Local overproduction of IL10 in astrocyte targeted IL10Tg mice modulates microglial response by modulating regulatory receptors TREM2 and CD200R following perforant pathway transection. — ASN Events
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  3. Local overproduction of IL10 in astrocyte targeted IL10Tg mice modulates microglial response by modulating regulatory receptors TREM2 and CD200R following perforant pathway transection.

Local overproduction of IL10 in astrocyte targeted IL10Tg mice modulates microglial response by modulating regulatory receptors TREM2 and CD200R following perforant pathway transection. (#332)

Kalpana Shrivastava 1 , Mireia Recasens 1 , Ian L. Campbell 2 , Berta Gonzalez 1 , Bernardo Castellano 1
  1. Universidad Autonoma de Barcelona, Spain, Barcelona, Spain
  2. School of Molecular Biosciences, University of Sydney, NSW, Sydney, Australia

Introduction: Interleukin-10 (IL-10) is a general anti-inflammatory cytokine that has been demonstrated in activated astrocytes and microglia after CNS injury but its specific role still remains ambiguous. One of the endogenous mechanisms regulating inflammation following brain injury is the expression of modulator and/or inhibitor membrane receptors. Recent studies demonstrate that TREM2-mediated phagocytic function of microglia/macrophages (MM) is required for debris clearance and maintenance of CNS tissue homeostasis. Moreover, CD200 receptor expressed on microglia is involved in maintaining the microglia in quiescent state.

Aim: We therefore, aimed to study the role of IL10 in modulating microglia using the axonal anterograde degeneration paradigm and to monitor TREM2 and CD200R expression as an effect of local astrocyte-targeted production of IL-10. We performed a perforant pathway transection (PPT) on adult GFAP-IL10 transgenic (Tg) mice and corresponding wild types (WT) littermates. Animals were intracardially perfused at 2,3,7,14 and 21 days post-lesion using 4% paraformaldehyde, brains frozen and sections cut in a cryostat. We performed single and double immunohistochemistry for microglia expressing TREM2 and CD200R.

Results: Our results show an increase in TREM2 and CD200R expression on microglia in the ipsilateral hemisphere of the Tg and WT animals especially in the molecular layer of the dennervated dentate gyrus after PPT and the expression was always higher in the Tg animal. We noticed that their expression is upregulated via local production of IL10 as seen by the activated phagocytosing phenotype (CD68high and CD16/32high) of microglia in the GFAP-IL10Tg animals. Furthermore, we found a possible feedback inhibition of IL10 as observed by a constant pSTAT3 expression in Tg mice.

Conclusions: Hence, specific modulation of these receptors and the anti-inflammatory cytokine IL10 with pharmacological tools represent a promising therapeutic strategy against CNS pathologies. Future studies are concentrated on evaluating the mechanism of action of IL10 in modulating these regulatory receptors following CNS injury.