Production of retinoic acid by antigen presenting cells in the healthy and inflamed human intestine.
Abstract
Murine small intestinal CD103+ dendritic cells (DCs) produce retinoic acid (RA) through
retinaldehyde dehydrogenase (RALDH) activity, thereby inducing ‘gut-homing’ α4β7 and
CCR9 on T cells they activate, enhancing TGF-β-mediated induction of Foxp3+
regulatory T cells and suppressing induction of pro-inflammatory TH17 cells. RALDH
activity of CD103+ DCs is reduced in mouse models of inflammatory bowel disease
(IBD) but the role of RALDH activity in human intestinal DCs in the pathogenesis of IBD
is undefined. This project aimed to determine the influence of inflammation on RALDH
activity of antigen presenting cell (APC) subsets including CD103+ DCs within human
distal intestinal mucosa. RALDH activity was identified by Aldefluor assay in intestinal
DCs (CD103+ and CD103- subsets) alongside ALDH1A2 expression in healthy controls.
In contrast with mouse models, RALDH activity was not reduced in CD103+ DCs from
IBD patients. An increased frequency of CD14+ macrophages (MФ) of IBD patients
displayed ALDH1A1-associated RALDH activity compared with healthy controls. Blood
CD14+ monocytes, putative precursors of intestinal CD14+ MФ, of healthy controls and
IBD patients displayed ALDH1A1-associated RALDH activity indicating RALDH is
systemically acquired by monocytes and upregulated within the mucosa of IBD
patients, or alternatively that RALDH+ monocytes are selectively recruited in IBD. In
vitro, inhibition of RA receptor-α signalling blocked GM-CSF-mediated differentiation of
TNFα-producing pro-inflammatory RALDH+ CD14+ MФ from monocytes, consistent with
enhanced RALDH activity of intestinal CD14+ MФ in IBD supporting a pro-inflammatory
phenotype. Soluble intestinal mediators including prostaglandin E2 suppressed RALDH
activity of MoDCs in vitro, whilst mediators from inflamed IBD mucosa conditioned
MoDCs to imprint enhanced levels of α4β7 expression on naive CD4+ T cells
independent of RALDH activity. This study provides the first systematic analysis of
RALDH activity in human intestinal APCs and indicates important distinctions between mouse models and human IBD
Authors
Sanders, Theodore JamesCollections
- Theses [4116]