PMID- 31461632
OWN - NLM
STAT- MEDLINE
DCOM- 20200723
LR  - 20200723
IS  - 1544-0591 (Electronic)
IS  - 0022-0345 (Linking)
VI  - 98
IP  - 12
DP  - 2019 Nov
TI  - TNF-alpha Suppresses Autophagic Flux in Acinar Cells in IgG4-Related Sialadenitis.
PG  - 1386-1396
LID - 10.1177/0022034519871890 [doi]
AB  - IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated 
      systemic fibroinflammatory disease that affects salivary glands and leads to 
      hyposalivation. Tumor necrosis factor-alpha (TNF-alpha) is a critical proinflammatory 
      cytokine involved in several salivary gland disorders, but its role and mechanism 
      regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-alpha 
      level was significantly increased in serum and submandibular gland (SMG) of 
      patients and that serum TNF-alpha level was negatively correlated with saliva flow 
      rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large 
      autophagic vacuoles, as well as dense fibrous bundles, decreased secretory 
      granules, widened intercellular spaces, swollen mitochondria, and expanded 
      endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in 
      patients' SMGs. TNF-alpha treatment led to elevated levels of LC3II and p62 in both 
      SMG-C6 cells and cultured human SMG tissues but did not further increase their 
      levels when combined with bafilomycin A1 treatment. Moreover, transfection of 
      Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux 
      after TNF-alpha treatment. Immunofluorescence imaging revealed that costaining of LC3 
      and the lysosomal marker LAMP2 was significantly decreased in patients, 
      TNF-alpha-treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in 
      autophagosome-lysosome fusion. Furthermore, the ratio of pro/mature cathepsin D 
      was elevated in vivo, ex vivo, and in vitro. TNF-alpha also appeared to induce 
      abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH 
      and LysoTracker DND-26 fluorescence intensity. In addition, TNF-alpha treatment 
      induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was 
      consistent with the changes observed in IgG4-RS patients. TNF-alpha increased the 
      phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and 
      inhibition of ERK1/2 by U0126 reversed TNF-alpha-induced TFEB redistribution, 
      lysosomal dysfunction, and autophagic flux suppression. These findings suggest 
      that TNF-alpha is a key cytokine related to acinar cell injury in IgG4-RS through 
      ERK1/2-mediated autophagic flux suppression.
FAU - Hong, X
AU  - Hong X
AD  - Department of Oral and Maxillofacial Surgery, Peking University Shenzhen 
      Hospital, Shenzhen Peking University, the Hong Kong University of Science and 
      Technology Medical Center, Shenzhen, P.R. China.
FAU - Min, S N
AU  - Min SN
AD  - Department of Oral and Maxillofacial Surgery, Peking University School and 
      Hospital of Stomatology, Beijing, P.R. China.
FAU - Zhang, Y Y
AU  - Zhang YY
AD  - Department of Oral and Maxillofacial Surgery, Peking University School and 
      Hospital of Stomatology, Beijing, P.R. China.
FAU - Lin, Y T
AU  - Lin YT
AD  - Department of Oral and Maxillofacial Surgery, Peking University Shenzhen 
      Hospital, Shenzhen Peking University, the Hong Kong University of Science and 
      Technology Medical Center, Shenzhen, P.R. China.
FAU - Wang, F
AU  - Wang F
AD  - Department of Oral and Maxillofacial Surgery, Peking University Shenzhen 
      Hospital, Shenzhen Peking University, the Hong Kong University of Science and 
      Technology Medical Center, Shenzhen, P.R. China.
FAU - Huang, Y
AU  - Huang Y
AD  - Department of Oral and Maxillofacial Surgery, Peking University School and 
      Hospital of Stomatology, Beijing, P.R. China.
FAU - Yu, G Y
AU  - Yu GY
AD  - Department of Oral and Maxillofacial Surgery, Peking University Shenzhen 
      Hospital, Shenzhen Peking University, the Hong Kong University of Science and 
      Technology Medical Center, Shenzhen, P.R. China.
AD  - Department of Oral and Maxillofacial Surgery, Peking University School and 
      Hospital of Stomatology, Beijing, P.R. China.
FAU - Wu, L L
AU  - Wu LL
AD  - Department of Physiology and Pathophysiology, Peking University School of Basic 
      Medical Sciences, Beijing, P.R. China.
FAU - Yang, H Y
AU  - Yang HY
AD  - Department of Oral and Maxillofacial Surgery, Peking University Shenzhen 
      Hospital, Shenzhen Peking University, the Hong Kong University of Science and 
      Technology Medical Center, Shenzhen, P.R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190828
PL  - United States
TA  - J Dent Res
JT  - Journal of dental research
JID - 0354343
RN  - 0 (Immunoglobulin G)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Acinar Cells/*cytology
MH  - *Autophagy
MH  - Humans
MH  - *Immunoglobulin G
MH  - MAP Kinase Signaling System
MH  - Sialadenitis/immunology/*physiopathology
MH  - Submandibular Gland/pathology
MH  - Tumor Necrosis Factor-alpha/*physiology
OTO - NOTNLM
OT  - ERK1/2
OT  - IgG4-related disease
OT  - acinar-cell injury
OT  - autophagy
OT  - lysosome
OT  - tumor necrosis factor-alpha
EDAT- 2019/08/29 06:00
MHDA- 2020/07/24 06:00
CRDT- 2019/08/29 06:00
PHST- 2019/08/29 06:00 [pubmed]
PHST- 2020/07/24 06:00 [medline]
PHST- 2019/08/29 06:00 [entrez]
AID - 10.1177/0022034519871890 [doi]
PST - ppublish
SO  - J Dent Res. 2019 Nov;98(12):1386-1396. doi: 10.1177/0022034519871890. Epub 2019 
      Aug 28.