NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

Abstract

Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H 2 O 2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35–40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4 −/− mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-β1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors.

Role of Nox4 in Mitigating Inflammation and Fibrosis in Dextran Sulfate Sodium–Induced Colitis

“…Although a previous study reported that Nox4 does not play a role in fibrosis in the murine colitis model, an increase in Tgfbr1 expression was detected with 2.5% DSS-induced colitis in Nox4 -/- mice. 17 This result was observed after 6 days of administration of 2.5% DSS and 9 days after recovery with water for only 3 days. In our experiment, 2.5% DSS was administered for 14 days, which induced more severe damage in the colon.…”

“…NOX4 expression is up-regulated in drug-resistant patients with UC 11 and fibrostenotic Crohn’s disease (CD), 12 and in dextran sulfate sodium (DSS)-induced murine colitis models. 13 , 14 Nox4 transcripts are detected at low levels in the normal colon, 15 but increase to protect against DSS-induced 16 , 17 and bacterial-induced 17 murine colitis. The related mechanism likely involves NOX4-driven ROS production, which induces the phosphorylation of p65 to activate nuclear factor-κB signaling and the M1 phenotype of intestinal macrophages, leading to mucosal barrier injury to promote colitis progression.…”

“…The related mechanism likely involves NOX4-driven ROS production, which induces the phosphorylation of p65 to activate nuclear factor-κB signaling and the M1 phenotype of intestinal macrophages, leading to mucosal barrier injury to promote colitis progression. 16 Although NOX4 has rarely been associated with the development of fibrogenic features in mouse colitis models, 17 the main pathologic mechanism contributing to fibrotic disease in the lung, 18 liver, 19 kidney, 20 and heart 21 is attributed to ROS-induced canonical transforming growth factor-β (TGF-β) signaling, and redox signaling driven by NOX4 is closely related to canonical TGF-β signaling to cause a TGF - β – induced profibrotic response. 22 However, the detailed molecular mechanism underlying fibrosis development in UC remains to be elucidated.…”

Emerging Pathological Engagement of Ferroptosis in Gut Diseases

“…In addition, other ferroptosis regulators, including NADPH oxidases [ 168 – 171 ] and CD44 [ 172 – 175 ], are evidenced to be associated with the pathogenesis of IBD in patients or in colitis models. These proteins, including P53, NRF2, NADPH oxidases, and CD44, are all multifaceted.…”

Intestinal stricture in Crohn's disease: A 2020 update

“…In addition to cytokines, factors involved in cellular oxidative stress, such as hyperactive nicotinamide adenine dinucleotide phosphate, also known as oxidase 4 (NOX4), has been found to have an impact on fibrosis of the intestine as well 21 . Another group 22 elaborated the role of NOX4 in intestinal fibrosis and revealed that NOX4 promoted recovery from colitis instead of fibrogenesis, possibly by affecting other antibacterial defense systems via NOX4‐dependent redox signaling or NOX4‐derived hydrogen peroxide. The breakdown of endoplasmic reticulum stress and the unfolded protein response could also drive the development of intestinal fibrosis 23 .…”