The Smoothened agonist SAG Modulates the Male and Female Peripheral Immune Systems Differently in an Immune Model of Central Nervous System Demyelination.

Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females.

Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination.

Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis.

P2X7 purinergic receptor plays a critical role in maintaining T-cell homeostasis and preventing lupus pathogenesis.

The severe lymphoproliferative and lupus diseases developed by MRL/ mice depend on interactions between the Fas mutation and MRL genetic background. Thus, the Fas mutation causes limited disease in C57BL/6 mice. We previously found that accumulating B220 CD4CD8 double negative (DN) T cells in MRL/ mice show defective P2X7 receptor ( P2X7)-induced cellular functions, suggesting that P2X7 contributes to T-cell homeostasis, along with Fas.

Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4 and CD8 T-Cell Subsets from B6 Mice Fed a High-Fat Diet.

We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4 and CD8 T cells to ATP depends on their stage of differentiation. Here, we show that CD4 and CD8 T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol.