Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation

Qiang Zhao,Qiang Zhao,Young-Min Han,Ping Song,Zhixue Liu,Ming-Hui Zou,Zuyi Yuan

doi:10.1038/s41467-022-28316-6

Abstract

In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 (Stk11) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor (Scf) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11-soluble-Scf axis as a potential cause of DC deficiency syndromes.

Highlights

In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step
In this study, we showed that serine/threonine kinase 11 (Stk11)-guided alternative splicing of stem cell factor (Scf) in bone marrow endothelial cells (EC) is strictly and non-cell-autonomously required for MDP differentiation into CDP
The most important finding from this study is that we have for the first-time presented evidence that Stk[11] in bone marrow ECs plays a key role in DC differentiation, and regulates immune homeostatic equilibrium

Summary

Introduction

Classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. DCs and monocytes share a common progenitor, the MDP, whereas a distinct progenitor, the CDP, is dedicated to DC production[7]. This cascade of DC progenitors has been identified, it remains unknown if the bone marrow niche regulates DC differentiation. Recent data demonstrate that Scf is strictly required for the long-term expansion of DC precursors[26], and c-Kit inhibitor fully blocks maturation of DCs from progenitors[27,28], how Scf regulates the proliferation and retention of the restricted DC progenitor population in the bone marrow is unknown

Methods

Results

Conclusion