S1PR1 regulates lymphatic valve development and prevents ileitis-independent tertiary lymphoid organ formation

Lymphatic vessels function throughout the body to drain interstitial fluids. Efficient lymph flow is ensured by lymphatic valves (LVs). However, the mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal-ileum draining lymphatic vessels were specifically dysfunctional, and tertiary lymphoid organs (TLOs) formed in this location. TLOs in the terminal ileum are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Sphingosine kinases 1 and 2 (SPHK1/2) are required for the synthesis of S1P, the ligand of S1PR1. Mice that lack Sphk1/2 in LECs recapitulate the LV and TLO phenotypes of mice that lack S1PR1. Mechanistically, S1PR1 regulates shear stress signaling and the expression of the valve-regulatory molecules F..., , # S1PR1 Regulates Lymphatic Valve Development And Tertiary Lymphoid Organ Formation

Dataset DOI: [10.5061/dryad.qbzkh18vj](10.5061/dryad.qbzkh18vj)

## Description of the data and file structure

S1pr1f/f and Tg(Prox1-CreERT2); S1pr1f/f mice were administered tamoxifen from postnatal days 1-7. Fecal pellets were collected from the mice for metagenomic sequencing when they were 10 months old. The file names and the genotypes of mice are provided below.

FS38995605- Tg(Prox1-CreERT2); S1pr1f/f

FS38995667- Tg(Prox1-CreERT2); S1pr1f/f

FS38995819- S1pr1f/f

FS38995785- S1pr1f/f

FS38995546- S1pr1f/f

### Files and variables

#### File: FS38995605.fastq

**Description:** Metagenomic analysis of fecal pellets from 10-month-old Tg(Prox1-CreERT2); S1pr1f/f (tamoxifen from P1-7) mouse-1.

#### File: FS38995667.fastq

**Description:** Metagenomic analysis of fecal pellets from 10-month-old Tg(Prox1-CreERT2); S1pr1f/f (tamoxifen from P1-7) mouse-2.

#### File: FS38995785.fastq

**Description:*...,