Abstract
Retinoic acid (RA)–producing CD103+ mature dendritic cells (DCs) in mesenteric lymph nodes (MLNs) play crucial roles in gut immunity. GM-CSF and RA contribute to the expression of the RA-producing enzyme ALDH1A2. However, additional signals appeared to be required for inducing ALDH1A2high mature DCs from immature DCs. We found here that TLR ligands (Ls) and immobilized E-cadherin could provide such signals in FLT3-L–generated bone marrow (BM)–derived DCs after treatment with GM-CSF and the RA receptor agonist Am80. The TLR-L-treated DCs produced proinflammatory cytokines unlike normal ALDH1A2high MLN-DCs, whereas the E-cadherin-treated DCs did not. Immobilized VCAM-1 and semaphorin 7 A exerted effects similar to those of E-cadherin. Soluble anti-integrin β1 antibodies or inhibitors of integrin signaling molecules suppressed the effects of these immobilized proteins, whereas immobilized anti-integrin β1 antibodies enhanced the GM-CSF/Am80-induced ALDH1A2 expression without inducing proinflammatory cytokines. Sequential stimulation of splenic pre-DCs with GM-CSF/Am80 and immobilized E-cadherin or anti-integrin β1 antibody also induced differentiation to mature DCs with high ALDH activity. The E-cadherin-treated BM-DCs induced gut-tropic Foxp3+ T cells and alleviated DSS–induced colitis, whereas the TLR-L-treated DCs aggravated DSS–induced colitis. The results suggest that integrin β1-mediated signals contribute to the differentiation and maturation of RA-producing anti-inflammatory DCs.
Highlights
Retinal dehydrogenases [e.g., aldehyde dehydrogenase 1A (ALDH1A)] encoded by the Aldh1a gene family are key enzymes that produce Retinoic acid (RA), and they are expressed in limited cell types
We found that stimulation of FMS-like tyrosine kinase 3 (FLT3)-L–generated bone marrow (BM)-dendritic cells (DCs) with GM-CSF/RA and subsequent stimulation with immobilized E-cadherin efficiently generate RA–producing anti-inflammatory DCs that can induce iTreg differentiation, and that integrin β1-mediated signals contribute to the E-cadherin effect
It is known that CD103+ mesenteric lymph nodes (MLNs)-DCs from steady-state SPF mice weakly produce proinflammatory cytokines upon stimulation through CD40 or with LPS9
Summary
Retinal dehydrogenases [e.g., aldehyde dehydrogenase 1A (ALDH1A)] encoded by the Aldh1a gene family are key enzymes that produce RA, and they are expressed in limited cell types. RA-producing DCs in MLNs, PPs, and the small intestinal lamina propria (LP) express the ALDH1A2 isoform at different levels[1,14,17]. These ALDH1A2+ DCs are included in the CD103+ DC subset[9,14]. We previously illustrated that the simultaneous stimulation of FLT3-L–generated BM-DCs with GM-CSF and Toll-like receptor (TLR)-L induced their maturation and high levels of ALDH1A2 expression[14]. We found that stimulation of FLT3-L–generated BM-DCs with GM-CSF/RA and subsequent stimulation with immobilized E-cadherin efficiently generate RA–producing anti-inflammatory DCs that can induce iTreg differentiation, and that integrin β1-mediated signals contribute to the E-cadherin effect
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