Type I interferon–related kidney disorders

Lodi, Lorenzo; Mastrolia, Maria Vincenza; Bello, Federica; Rossi, Giovanni Maria; Angelotti, Maria Lucia; Crow, Yanick J.; Romagnani, Paola; Vaglio, Augusto

doi:10.1016/j.kint.2022.02.031

Cited by 36 publications

(26 citation statements)

References 153 publications

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“…IFN-I might cause collapsing glomerulopathy, proliferative nephritis and vasculitis in cases of SAVI and coatomer protein subunit-α syndrome 113 . The cGAS–STING pathway might also contribute to acute kidney injury (AKI) and CKD characterized by kidney fibrosis 114 .…”

Section: Cgas–sting In Diseasementioning

confidence: 99%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

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Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

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Section: Cgas–sting In Diseasementioning

confidence: 99%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

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“…Recent emphasis on the association of enhanced IFN-I signaling and kidney injury has focused on glomerular injury ( Lodi et al, 2022 ), without considering associated tubulointerstitial injury. Pathway enrichment analysis in a previously reported transcriptomics dataset of murine folic acid nephropathy (FAN) ( González-Guerrero et al, 2018 ; Fontecha-Barriuso et al, 2019 ) identified multiple activated upstream regulators of the TI-IFN pathway having an absolute z-score > 2.0 and p -value < 0.05 ( Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, whether these interactions contribute to regulating kidney inflammation is unclear, despite the observation that human diseases associated with kidney injury, e.g. viral infections, type I interferonopathies, and autoimmune conditions (e.g., systemic lupus erythematosus) are characterized by enhanced IFN-I signaling ( Lodi et al, 2022 ). Thus, although some reports have highlighted the contribution of T1-IFNs in postischemic kidney injury or lupus nephritis ( Freitas et al, 2011 ; Ding et al, 2021 ), the regulation and function of molecular routes upstream or downstream of TI-IFN remain mostly unexplored in intrinsic kidney cells and kidney injury, especially in tubular cells and tubulointerstitial disease.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury

et al. 2022

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The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNα/β binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKε and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKε-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKε with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKε siRNA did not. In vivo, kidney IFNAR and IFNβ were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKε with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKε with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury.

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“…Histological signs of immunological activity, such as the presence of deposits of complement factors and immune complexes, their isotypes and their clonality, as well as ultrastructural changes observed with electron microscopy, provide further clues to the underlying cause of GN. For example, expansion of the cisternae of the endoplasmic reticulum, named ‘tubuloreticular structures’, in glomerular cells is considered an ultrastructural hallmark of type I interferon signalling, although the molecular mechanisms remain unknown 17 . However, lesion patterns such as immune complex GN, complement factor C3 GN (C3GN) and pauci-immune GN are nonspecific regarding the underlying pathophysiology.…”

Section: Clinical Presentation and Diagnosis Of Gnmentioning

confidence: 99%

“…Podocyte loss is associated with proteinuria and irreversible glomerulosclerosis 45 . Type I interferons induce podocyte death by catastrophic mitosis and block the differentiation of local podocyte progenitors into new podocytes 17 , 46 , 47 . By contrast, activation of immature progenitors among the parietal epithelial cells can result in the formation of hyperplastic lesions that obliterate the Bowman space and block glomerular filtration loss 48 .…”

Section: Infection-related Gnmentioning

confidence: 99%

Glomerulonephritis: immunopathogenesis and immunotherapy

et al. 2023

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‘Glomerulonephritis’ (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.

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Type I interferon–related kidney disorders

Cited by 36 publications

References 153 publications

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Role of the cGAS–STING pathway in systemic and organ-specific diseases

Crosstalk between TBK1/IKKε and the type I interferon pathway contributes to tubulointerstitial inflammation and kidney tubular injury

Glomerulonephritis: immunopathogenesis and immunotherapy

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