Contribution of SIGLEC-11 and SIGLEC-16 receptors to neuro-inflammation and neurodegeneration

Abstract

Brain aging is a multifactorial process including accumulation of aged lipids and proteins, neuroinflammation and loss of neurons. SIGLEC-11 and SIGLEC-16 are paired opposite inhibitory- versus activatory-signaling receptors on human microglia without any direct homology in mice. Contribution of these paired receptors to brain aging is still unclear. <br /> In this study, the effect of these paired receptors during normal aging was investigated at two different time points (6 and 24 months of age) in humanized inhibitory-signaling SIGLEC-11 versus activatory-signaling SIGLEC-16 transgenic (tg) mice, that ectopically were expressing the respective human receptors in microglia and macrophages. Immunohistochemical analysis of hippocampus and substantia nigra showed that the number of Iba1-positive cells was increased at the age of 24 months in SIGLEC-16 compared to the SIGLEC-11 tg mice and wildtype group. In addition, protein levels of Cd68 were increased in SIGLEC-16 tg mice at 24 months versus the other both groups. In line with the protein level results, gene transcription of the microglial markers, Iba1 and Cd68, increased in SIGLEC-16 tg at 24 months old versus the wildtype control and SIGLEC-11 tg groups. Results also demonstrated that 6 months old SIGLEC-11 tg mice have lower gene transcription levels of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β and the complement proteins including C3 and C4 compared to SIGLEC-16 tg mice. Furthermore, oxidative markers presented higher levels in SIGLEC-16 tg at an age of 24 months compared to the other groups at the similar age. Moreover, 24 months old SIGLEC-16 tg mice showed increased loss of neurons in the hippocampus compared to the wildtype control and SIGLEC-11 tg mice. In parallel, staining of pre- and post-synaptic markers demonstrated higher number of synapses in SIGLEC-11 tg mice at 6 months of age compared to the other experimented groups. Results suggest that activation of microglia as well as the complement cascade are better controlled in SIGLEC-11 tg mice and that increased inflammation might contribute to loss of neurons in SIGLEC-16 tg mice. <br /> Taken together, our study described inhibitory-signaling SIGLEC-11 as neuro- and synapse-protective receptor through aging, while activatory-signaling SIGLEC-16 promotes inflammation and neuronal loss.