Bull, E. | bioRxiv Science

bioRxiv2022

Therapeutic activation of endothelial sphingosine 1-phosphate receptor-1 by chaperone-bound S1P suppresses proliferative retinal vasculopathy

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator that signals via G protein-coupled S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is largely unexplored. Here we show in a mouse model of oxygen-induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout (KO) of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom KO mice which lack HDL-bound S1P while they are suppressed in Apom TG mice which has more circulating HDL-S1P. These results suggest that circulating HDL-S1P activation of endothelial S1PR1 specifically suppresses proliferative retinal vasculopathy. Moreover, systemic administration of ApoM-Fc-bound S1P or a small molecule Gi-biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL-S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetes and aging.

pathology↗

bioRxiv2019

The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled acute MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In a demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In a post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.

immunology↗