PMID- 35288362
OWN - NLM
STAT- MEDLINE
DCOM- 20220606
LR  - 20230703
IS  - 1878-1810 (Electronic)
IS  - 1931-5244 (Print)
IS  - 1878-1810 (Linking)
VI  - 245
DP  - 2022 Jul
TI  - Cell type-specific mechanistic target of rapamycin-dependent distortion of 
      autophagy pathways in lupus nephritis.
PG  - 55-81
LID - S1931-5244(22)00047-0 [pii]
LID - 10.1016/j.trsl.2022.03.004 [doi]
AB  - Pro-inflammatory immune system development, metabolomic defects, and deregulation 
      of autophagy play interconnected roles in driving the pathogenesis of systemic 
      lupus erythematosus (SLE). Lupus nephritis (LN) is a leading cause of morbidity 
      and mortality in SLE. While the causes of SLE have not been clearly delineated, 
      skewing of T and B cell differentiation, activation of antigen-presenting cells, 
      production of antinuclear autoantibodies and pro-inflammatory cytokines are known 
      to contribute to disease development. Underlying this process are defects in 
      autophagy and mitophagy that cause the accumulation of oxidative 
      stress-generating mitochondria which promote necrotic cell death. Autophagy is 
      generally inhibited by the activation of the mammalian target of rapamycin 
      (mTOR), a large protein kinase that underlies abnormal immune cell lineage 
      specification in SLE. Importantly, several autophagy-regulating genes, including 
      ATG5 and ATG7, as well as mitophagy-regulating HRES-1/Rab4A have been linked to 
      lupus susceptibility and molecular pathogenesis. Moreover, genetically-driven 
      mTOR activation has been associated with fulminant lupus nephritis. mTOR 
      activation and diminished autophagy promote the expansion of pro-inflammatory 
      Th17, Tfh and CD3(+)CD4(-)CD8(-) double-negative (DN) T cells at the expense of 
      CD8(+) effector memory T cells and CD4(+) regulatory T cells (Tregs). mTOR 
      activation and aberrant autophagy also involve renal podocytes, mesangial cells, 
      endothelial cells, and tubular epithelial cells that may compromise end-organ 
      resistance in LN. Activation of mTOR complexes 1 (mTORC1) and 2 (mTORC2) has been 
      identified as biomarkers of disease activation and predictors of disease flares 
      and prognosis in SLE patients with and without LN. This review highlights recent 
      advances in molecular pathogenesis of LN with a focus on immuno-metabolic 
      checkpoints of autophagy and their roles in pathogenesis, prognosis and selection 
      of targets for treatment in SLE.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Caza, Tiffany
AU  - Caza T
AD  - Arkana Laboratories, Little Rock, Arkansas.
FAU - Wijewardena, Chathura
AU  - Wijewardena C
AD  - Departments of Medicine, State University of New York, Upstate Medical 
      University, College of Medicine, Syracuse, New York.
FAU - Al-Rabadi, Laith
AU  - Al-Rabadi L
AD  - Department of Medicine, University of Utah, Salt Lake City, Utah.
FAU - Perl, Andras
AU  - Perl A
AD  - Departments of Medicine, State University of New York, Upstate Medical 
      University, College of Medicine, Syracuse, New York; Biochemistry and Molecular 
      Biology, Neuroscience and Physiology, State University of New York, Upstate 
      Medical University, College of Medicine, Syracuse, New York; Medicine, 
      Microbiology and Immunology, Biochemistry and Molecular Biology, State University 
      of New York, Upstate Medical University, College of Medicine, Syracuse, New York. 
      Electronic address: perla@upstate.edu.
LA  - eng
GR  - R01 AI122176/AI/NIAID NIH HHS/United States
GR  - R34 AI141304/AI/NIAID NIH HHS/United States
GR  - U01 AR076092/AR/NIAMS NIH HHS/United States
GR  - R01 AI048079/AI/NIAID NIH HHS/United States
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20220312
PL  - United States
TA  - Transl Res
JT  - Translational research : the journal of laboratory and clinical medicine
JID - 101280339
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Autophagy
MH  - Endothelial Cells/metabolism
MH  - Humans
MH  - *Lupus Erythematosus, Systemic
MH  - *Lupus Nephritis/pathology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC9240418
MID - NIHMS1815833
COIS- The authors have read the journal's policy on disclosure of potential conflicts 
      of interest and declare no conflicts of interest. All authors have read the 
      journal's authorship agreement and that the manuscript has been reviewed by and 
      approved by all named authors.
EDAT- 2022/03/16 06:00
MHDA- 2022/06/07 06:00
PMCR- 2023/07/01
CRDT- 2022/03/15 05:42
PHST- 2022/01/24 00:00 [received]
PHST- 2022/03/07 00:00 [revised]
PHST- 2022/03/07 00:00 [accepted]
PHST- 2022/03/16 06:00 [pubmed]
PHST- 2022/06/07 06:00 [medline]
PHST- 2022/03/15 05:42 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - S1931-5244(22)00047-0 [pii]
AID - 10.1016/j.trsl.2022.03.004 [doi]
PST - ppublish
SO  - Transl Res. 2022 Jul;245:55-81. doi: 10.1016/j.trsl.2022.03.004. Epub 2022 Mar 
      12.