TLR9-signaling is required for turning retinoic acid into a potent stimulator of RP105 (CD180)-mediated proliferation and IgG synthesis in human memory B cells

Eriksen, Agnete Bratsberg; Indrevær, Randi Larsen; Holm, Kristine Lillebø; Landskron, Johannes; Blomhoff, Heidi Kiil

doi:10.1016/j.cellimm.2012.09.003

Cited by 18 publications

(36 citation statements)

References 44 publications

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“…8,9 Having previously demonstrated the stimulatory effect of RA on IgG-production in normal human B cells activated via TLR9 alone or in combination with CD180, 23,24,31 we here investigated the possible involvement of autophagy in this process. The MAP1LC3/LC3 (microtubuleassociated protein 1 light chain 3) protein is a widely used and accepted marker of phagophores and autophagosomes, 32 and is commonly used to monitor the levels of autophagy.…”

Section: Resultsmentioning

confidence: 99%

“…Given the recently acknowledged importance of autophagy in plasma cell formation and Ig secretion, 8,9 and having previously shown that RA potentiates IgG secretion in human peripheral B cells stimulated via TLRs, 23,24,31 we next asked whether autophagy was involved in RA-mediated induction of IgG. To this end, B cells were transfected with siRNA against ULK1 or with a control siRNA, and as shown in Figure 6A, knocking down ULK1 reversed the RA-induced formation of LC3B-II.…”

Section: Ra-mediated Secretion Of Igg Involves Autophagymentioning

confidence: 99%

“…We have previously shown that RA enhances TLR9-and CD180-mediated IgG production in both na€ ıve and memory B cells, with the strongest effects seen in memory B cells. 23 In order to verify that the effects of RA on autophagy and ULK1 could be seen both in the na€ ıve (CD19 C CD27 -) and memory (CD19 C CD27 -) subsets of B cells, the CD19 C B cells were fractionated into CD27 C and CD27 -B cells and the 2 cell fractions subjected to analysis of the LC3B-II/ LC3B-I ratio and ULK1 expression. As shown in Figure 4A and B, RA enhanced the LC3B-II/LC3B-I ratio and the ULK1 expression in both subpopulations.…”

Section: Colocalization Of Autophagosomes and Lysosomes Is Enhanced Bmentioning

confidence: 99%

“…21 TLR9, located in the membrane of endosomes, recognizes CpG motifs of bacterial DNA and is activated in vitro by synthetic unmethylated CpG oligomers. 22 We 23,24 and others 25 have revealed that TLR9-mediated activation of B cells can be significantly enhanced by costimulation with antibodies against the TLR-related receptor CD180/ RP105. CD180 was originally identified as a radio-protective protein of 150 kDa 26,27 and the in vivo ligand for CD180 remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…17,29,30 We have previously shown that the vitamin A metabolite RA is able to potentiate the interplay between innate and adaptive B cell responses by enhancing TLR9-mediated and TLR9-and CD180-mediated activation of human B cells 23,31 with a particularly strong impact on TLR9-and CD180-mediated differentiation of B cells into Ig-secreting plasma cells. 23 Given the recent awareness of the importance of autophagy for the generation and maintenance of plasma cells, 8,9 we here explored the involvement of autophagy in RA-mediated differentiation of B cells into Ig-secreting cells. We revealed that RA noticeably enhances autophagy in TLR9-and CD180-stimulated human peripheral blood B cells, and we suggest that RA exerts this effect at least partly by increasing the transcription of the gene encoding the autophagy-inducing protein ULK1 (unc-51 like autophagy activating kinase 1).…”

Section: Introductionmentioning

confidence: 99%

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Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

et al. 2015

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(2015) Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy, Autophagy, 11:3, 460-471, DOI: 10.1080/15548627.2015 Keywords: antibody secretion, autophagy, B lymphocytes, CD180, plasma cell differentiation, retinoic acid, RP105, TLR9, ULK1Abbreviations: ATG, autophagy-related; BDS, bright detail similarity; CD180, CD180 molecule; CVID, common variable immune deficiency; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; IL, interleukin; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3 b; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PAMP, pathogen-associated molecular pattern, PML/RARA, promyelocytic leukemia/ retinoic acid receptor a; RA, all-trans retinoic acid; RAR, retinoic acid receptor; SQSTM1, sequestosome 1; TLR, toll-like receptor; ULK1, unc-51 like autophagy activating kinase 1.In the present study we have established a vital role of autophagy in retinoic acid (RA)-induced differentiation of tolllike receptor (TLR)-stimulated human B cells into Ig-secreting cells. Thus, RA enhanced autophagy in TLR9-and CD180-stimulated peripheral blood B cells, as revealed by increased levels of the autophagosomal marker LC3B-II, enhanced colocalization between LC3B and the lysosomal marker Lyso-ID, by a larger percentage of cells with more than 5 characteristic LC3B puncta, and by the concomitant reduction in the level of SQSTM1/p62. Furthermore, RA induced expression of the autophagy-inducing protein ULK1 at the transcriptional level, in a process that required the retinoic acid receptor RAR. By inhibiting autophagy with specific inhibitors or by knocking down ULK1 by siRNA, the RAstimulated IgG production in TLR9-and CD180-mediated cells was markedly reduced. We propose that the identified prominent role of autophagy in RA-mediated IgG-production in normal human B cells provides a novel mechanism whereby vitamin A exerts its important functions in the immune system.

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Section: Resultsmentioning

confidence: 99%

Section: Ra-mediated Secretion Of Igg Involves Autophagymentioning

confidence: 99%

Section: Colocalization Of Autophagosomes and Lysosomes Is Enhanced Bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

et al. 2015

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Retinoids as an Immunity-modulator in Dermatology Disorders

Chen

Zhu

et al. 2019

Arch. Immunol. Ther. Exp.

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Cellular growth and tube formation of HTR8/SVneo trophoblast: effects of exogenously added fatty acid-binding protein-4 and its inhibitor

et al. 2017

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Adequate placental angiogenesis is critical for the establishment of the placental circulation and thus for normal feto-placental growth and development. Fatty acid-binding protein-4 (FABP4) plays a pro-angiogenic role in endothelial cells; however, very little information is available in placental first trimester trophoblast cells. Here we report that exogenously added FABP4 (exo-FABP4) stimulated tube formation (as a measure of in vitro angiogenesis) in HTR8/SVneo trophoblastic cells. HTR-8/SVneo cells were incubated in the presence of exogenously added FABP4 at different concentrations and time points. Cellular growth, proliferation, in vitro tube formation, expression of growth stimulatory-, fatty acid transporters, and angiogenic genes were investigated. Internalization of exo-FABP4 was carried out using immunocytochemistry. Radioactive fatty acid uptake was determined in the presence and absence of FABP4 metabolic inhibitor. Exo-FABP4 (10-100 ng/ml) stimulated proliferation of HTR8/SVneo cells as compared to control. Exo-FABP4 dose dependently increased growth and viability of the cells to the similar extent as done by 50 µM of arachidonic acid. Exo-FABP4-induced tube formation and proliferation were significantly inhibited by FABP4 (BMS309403) inhibitor. Exo-FABP4 stimulated the expression of growth stimulatory genes such as tissue inhibitor of matrix metalloproteinases-1 (TIMP1), insulin-like growth factor 1 (IGF1), and also prokineticin 2 (PROK2), the pro-angiogenic mediators in these cells. In addition, expressions of genes associated with proliferation and differentiation such as sonic hedgehog (SHH) and WNT1 inducible signalling pathway protein 1 (WISP1) were significantly expressed when cells were exposed to exo-FABP4. Our findings reveal a pro-angiogenic role of FABP4 in first trimester placental trophoblast cells and its regulation may have impact in placental physiology.

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TLR9-signaling is required for turning retinoic acid into a potent stimulator of RP105 (CD180)-mediated proliferation and IgG synthesis in human memory B cells

Cited by 18 publications

References 44 publications

Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy

Retinoids as an Immunity-modulator in Dermatology Disorders

Cellular growth and tube formation of HTR8/SVneo trophoblast: effects of exogenously added fatty acid-binding protein-4 and its inhibitor

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