title: Beta 1-integrin ligation and TLR ligation enhance GM-CSF-induced ALDH1A2 expression in dendritic cells, but differentially regulate their anti-inflammatory properties.
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 ALDH1A2highmature 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 ALDH1A2highMLN-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.
authors.affiliation: Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.|Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yokota-Nakatsuma
authors.affiliation: Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.|Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Ohoka
authors.affiliation: Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.|Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.|Institute of Neuroscience, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.
authors.forename: Si-Young
authors.initials: SY
authors.lastname: Song
authors.affiliation: Laboratory of Immunology, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki-shi, Kagawa, Japan.|Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Iwata
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050697:Retinal Dehydrogenase; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D015820:Cadherins; D016207:Cytokines; D019012:Integrin beta1; D051193:Toll-Like Receptors; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase