Retinoic acid-induced IgG production in TLR-activated human primary B cells involves ULK1-mediated autophagy.
In the present study we have established a vital role of autophagy in retinoic acid (RA)-induced differentiation of toll-like 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 RA-stimulated 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.
a Department of Biochemistry ; Institute of Basic Medical Sciences; University of Oslo ; Oslo , Norway.
Agnete Bratsberg
AB
Eriksen
Maria Lyngaas
ML
Torgersen
Kristine Lillebø
KL
Holm
Greger
G
Abrahamsen
Anne
A
Spurkland
Jan Øivind
JØ
Moskaug
Anne
A
Simonsen
Heidi Kiil
HK
Blomhoff
D015703:Antigens, CD / Q000378:metabolism; D018941:Antigens, CD19 / Q000378:metabolism; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D018899:CpG Islands; D006801:Humans; D007107:Immune System; D007074:Immunoglobulin G / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008247:Lysosomes / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000737:chemistry*
D015703:Antigens, CD; D018941:Antigens, CD19; C092722:CD180 protein, human; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014212:Tretinoin; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human
ATG, autophagy-related; B lymphocytes; BDS, bright detail similarity; CD180; CD180, CD180 molecule; CVID, common variable immune deficiency; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; Ig, immunoglobulin; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 β; MTOR, mechanistic target of rapamycin (serine/threonine kinase); PAMP, pathogen-associated molecular pattern, PML/RARA, promyelocytic leukemia/ retinoic acid receptor α; RA, all-trans retinoic acid; RAR, retinoic acid receptor; RP105; SQSTM1, sequestosome 1; TLR, toll-like receptor; TLR9; ULK1; ULK1, unc-51 like autophagy activating kinase 1; antibody secretion; autophagy; plasma cell differentiation; retinoic acid