REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1β Inflammatory Response in Active Ulcerative Colitis

Abstract

Infiltration of neutrophils into colonic mucosa has been associated with the severity of ulcerative colitis (UC). We investigated the effect of disease microenvironment on the release of neutrophil extracellular traps (NETs) as well as the involved mechanisms in NETosis and whether certain NET proteins are correlated with disease phenotype. Peripheral blood neutrophils, sera, and colonic tissue were collected from treatment-naive and mesalazine-treated patients with active UC, treatment-naive patients with active Crohn's disease, patients suffering from infectious colitis, or healthy individuals (controls). Analysis of colonic biopsy specimens and peripheral blood neutrophils for the presence of NET-related markers using immunofluorescence confocal microscopy, ELISA, immunoblotting, flow cytometry, and quantitative PCR were performed. In vitro cell and tissue culture systems were further deployed. The local inflammatory response in colon in UC, but not Crohn's disease, is characterized by the presence of NETs carrying bioactive IL-1β and thrombogenic tissue factor. The inflammatory environment of UC is able to induce neutrophil activation, IL-1β expression, and NET release, as shown both ex vivo and in vitro. REDD1 expression, as a mediator linking inflammation, autophagy, and NET release, was also specifically associated with the inflammatory response of UC. We show that neutrophil expression of REDD1 in colon tissue and the presence of IL-1β in neutrophils/NETs provide candidate biomarkers for the differential diagnosis of inflammatory colitis and possible targets for the treatment of UC, suggesting that UC shares common features with autoinflammatory disorders.

Suppression of REDD1 attenuates oxygen glucose deprivation/reoxygenation‐evoked ischemic injury in neuron by suppressing mTOR‐mediated excessive autophagy

“…Neuroinflammation is also strongly involved in cerebral I/R progression . Accumulating evidence implicates REDD1 in the activation of inflammatory pathways . Accordingly, further study will focus on the interplay between REDD1 and inflammation in the development of brain I/R.…”

Autophagy in Neutrophils: From Granulopoiesis to Neutrophil Extracellular Traps

“…Moreover, recent clinical and experimental studies suggest that in the context of different diseases, neutrophils release NETs that are qualitatively different and express disease-related bioactive proteins, determined by the disease inflammatory environment. For example, IL-1β-bearing NETs characterize inflammatory flares of typical autoinflammatory diseases such familial Mediterranean fever (FMF) and Still’s disease ( Apostolidou et al, 2016 ; Skendros et al, 2017 ; Angelidou et al, 2018 ). Autoantigens in NETs have been associated with autoimmune diseases such as lupus, rheumatoid arthritis and ANCA-associated vasculitis ( Lande et al, 2011 ; Khandpur et al, 2013 ; Tang et al, 2015 ; Lood et al, 2016 ), and exposure of thrombogenic tissue factor (TF) through NETs drives several thromboinflammatory conditions ( Kambas et al, 2012a , b , 2014 ; von Brühl et al, 2012 ; Stakos et al, 2015 ; Chrysanthopoulou et al, 2017 ).…”

“…Increasing evidence indicates the pathogenic role of autophagy-mediated NETs in various clinical models of acute or chronic sterile inflammation, including common IL-1β-mediated autoinflammatory diseases ( Mitroulis et al, 2011a ; Apostolidou et al, 2016 ; Papagoras et al, 2017 ; Skendros et al, 2017 ), ANCA-associated vasculitis ( Kambas et al, 2014 ; Tang et al, 2015 ; Sha et al, 2016 ), active ulcerative colitis ( Angelidou et al, 2018 ), severe asthma ( Pham et al, 2017 ), cancer inflammation ( Boone et al, 2015 ), and IL-17-mediated disorders such as fibrosis ( Chrysanthopoulou et al, 2014 ) and epidermal hyperplasia ( Suzuki et al, 2016 ).…”

“…REDD1/mTOR/autophagy/NETosis pathway has been also associated with the IL-1β response in active ulcerative colitis supporting the autoinflammatory nature of this inflammatory bowel disease. Notably, in contrast to active Crohn’s disease, REDD1 or Beclin-1 expression in colonic neutrophils, and NETosis are diminished according to the distance from the inflamed intestinal area, suggesting that neutrophil autophagy could be a candidate diagnostic and disease severity target in ulcerative colitis ( Angelidou et al, 2018 ).…”

Danger signals in oral cavity-related diseases

“…). While DAMPS such as HGMB1 and histones released by injured liver hepatocytes can induce NET formation through TLR activation, and NETs with associated IL‐1β are linked with active ulcerative colitis, to our knowledge the involvement of DAMPs in NET formation within the oral cavity is currently unknown.…”