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 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.

Single nucleus RNA-sequencing reveals altered intercellular communication and dendritic cell activation in nonobstructive hypertrophic cardiomyopathy

“…A role for dendritic cells in human heart failure is less well-established, although a trend toward elevated numbers in blood has been reported 30 . Integrin-mediated signaling has been shown to be an important determinant of dendritic cell function, with ITGB1 determining dendritic morphology 31 and promoting an anti-inflammatory phenotype in bone-marrow-derived dendritic cells 32 . Our data linking dendritic cells to fibroblasts, smooth muscle cells and pericytes by ITGB1 signaling is novel and suggests an important role for these cells in the pathological hypertrophy, cardiac fibrosis and vascular abnormalities seen in nonobstructive HCM.…”

Lipopolysaccharide impacts murine CD103+ DC differentiation, altering the lung DC population balance

“…Pre‐DCs do not express CD103 and the exact mechanisms by which tissue DCs express this integrin are not well known . Previous studies demonstrated that GM‐CSF stimulation induces CD103 expression on BM derived DC in vitro and that GM‐CSF deficient mice were also deficient for CD103 + DCs .…”

“…Pulmonary DCs are recruited from blood precursors (or pre‐DCs) , which arise in the BM to enter blood as CD103‐negative pre‐DCs . Previous studies reported that GM‐CSF upregulates CD103 expression on BM‐derived DCs differentiated with FLT3‐L in vitro, and that GM‐CSF or GM‐CSF receptor deficient mice display altered CD103 expression on DC1s in several organs, including the lung . Interestingly, previous reports show that LPS blocks CD103 expression induced by retinoic acid on human monocyte derived‐DCs .…”

Single Nucleus RNA-sequencing Reveals Altered Intercellular Communication and Dendritic Cell Activation in Nonobstructive Hypertrophic Cardiomyopathy

“…A role for dendritic cells in human heart failure is less well-established, although a trend toward elevated numbers in blood has been reported [ 37 ]. Integrin-mediated signaling has been shown to be an important determinant of dendritic cell function, with ITGB1 determining dendritic morphology [ 38 ] and promoting an anti-inflammatory phenotype in bone-marrow-derived dendritic cells [ 39 ]. Our data linking dendritic cells to fibroblasts, smooth muscle cells and pericytes by potential ITGB1 signaling is novel and suggests an important role for these cells in the pathological hypertrophy, cardiac fibrosis and vascular abnormalities seen in nonobstructive HCM.…”