Amino Acid Metabolism Inhibits Antibody-Driven Kidney Injury by Inducing Autophagy

Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun; Gnana-Prakasam, Jaya P.; Veeranan-Karmegam, Rajalakshmi; Huang, Lei; Ravishankar, Buvana; Bradley, Jeremy T.; Kvirkvelia, Nino; McMenamin, Malgorzata; Xiao, Wei; Kleven, Daniel; Mellor, Andrew L.; Madaio, Michael P.; McGaha, Tracy L.

doi:10.4049/jimmunol.1500277

Cited by 41 publications

(37 citation statements)

References 62 publications

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“…We previously demonstrated that IL-10 was responsible for IDO1 induction in cells of lepromatous patients [55]. More recently, the IDO1–EIF2AK4/GCN2 axis has been associated with the induction of autophagy in renal cells, enacting a beneficial role in controlling fatal inflammation in mice [56]. The objective of our future studies is to investigate the IDO1–EIF2AK4/GCN2 axis in L-lep leprosy and the immune regulatory components associated with autophagy induction or blockage.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.

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Section: Discussionmentioning

confidence: 99%

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

et al. 2017

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“…IDO supports interleukin (IL)-6 production through GCN2 activation and was revealed to affect myeloid-derived suppressor cell function and tumor progression (15). A previous study in nephritis mouse models, conducted by Chaudhary et al (16), suggested that kidney injury of mice were improved by amino acid metabolism and protected from the autophagic response. The IFN-γ-mediated induction of IDO activity with subsequent activation of GCN2 is implied in the metabolic signaling process.…”

Section: Ido Depletes Tryptophan and Produces Bioactive Downstream Mementioning

confidence: 99%

Indoleamine 2, 3-dioxygenase regulation of immune response (Review)

Gong

Liu

2018

Mol Med Report

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Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation. The present review evaluates the recent progress in elucidating how catabolism of tryptophan regulated by IDO modulates the immune response to inflammatory and immunological signals. Blocking this pathway may be a novel adjuvant therapeutic strategy for clinical application in immunotherapy.

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“…154 Interestingly, the indoleamine 2,3-dioxygenasegeneral control nonderepressible 2 pathway in podocytes and other cells was suggested to be a critical negative feedback cascade that limits inflammatory renal injuries by inducing autophagy in a model of nephrotoxic serum nephritis. 155 Increasing kidney indoleamine 2,3-dioxygenase 1 activity or treating mice with a general control nonderepressible 2 agonist induced autophagy and protected mice from nephritic kidney damage. Interestingly, kidneys from patients with antibody-driven nephropathy showed increased indoleamine 2,3-dioxygenase 1 abundance and stress gene expression, suggesting interplay between autophagy and interferong-mediated protective feedback cascade.…”

Section: Autophagy In Aging and Diseased Kidneysmentioning

confidence: 99%

“…Interestingly, kidneys from patients with antibody-driven nephropathy showed increased indoleamine 2,3-dioxygenase 1 abundance and stress gene expression, suggesting interplay between autophagy and interferong-mediated protective feedback cascade. 155 Autophagy in DN. DN is the leading cause of end-stage renal disease in industrialized countries.…”

Section: Autophagy In Aging and Diseased Kidneysmentioning

confidence: 99%

Autophagy in kidney disease and aging: lessons from rodent models

Lenoir¹,

Tharaux²,

Huber³

2016

Kidney International

122

110

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Autophagy is a highly regulated lysosomal protein degradation pathway that removes protein aggregates and damaged or excess organelles to maintain intracellular homeostasis and cell integrity. Dysregulation of autophagy is involved in the pathogenesis of a variety of metabolic and age-related diseases. Growing evidence suggests that autophagy is implicated in cell injury during renal diseases, both in the tubulointerstitial compartment and in glomeruli. Nevertheless, the impact of autophagy on renal disease progression and aging is still not fully understood. This review summarizes the recent advances in understanding the role of autophagy for kidney disease and aging.

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Amino Acid Metabolism Inhibits Antibody-Driven Kidney Injury by Inducing Autophagy

Cited by 41 publications

References 62 publications

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

Indoleamine 2, 3-dioxygenase regulation of immune response (Review)

Autophagy in kidney disease and aging: lessons from rodent models

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