4.8 Article

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

Journal

AUTOPHAGY
Volume 11, Issue 3, Pages 460-471

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1009797

Keywords

antibody secretion; autophagy; B lymphocytes; CD180; plasma cell differentiation; retinoic acid; RP105; TLR9; ULK1; 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; microtubule-associated protein 1 light chain 3; MTOR; mechanistic target of rapamycin (serine; threonine kinase); PAMP; pathogen-associated molecular pattern; PML; RARA; promyelocytic leukemia; retinoic acid receptor; RA; all-trans retinoic acid; RAR; retinoic acid receptor; SQSTM1; sequestosome 1; TLR; toll-like receptor; ULK1; unc-51 like autophagy activating kinase 1

Categories

Funding

  1. University of Oslo
  2. Freia Research Foundation
  3. Jahre Research Foundation
  4. Research Council of Norway
  5. Norwegian Cancer Society

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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.

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