Deficient Production of Reactive Oxygen Species Leads to Severe Chronic DSS-Induced Colitis in Ncf1/p47phox-Mutant Mice

Rodrigues-Sousa, Tiago; Ladeirinha, Ana; Santiago, Ana Raquel; Carvalheiro, Helena; Raposo, Bruno; Alarcão, Ana; Cabrita, António; Holmdahl, Rikard; Carvalho, Lina; Souto-Carneiro, Margarida

doi:10.1371/journal.pone.0097532

Cited by 27 publications

(23 citation statements)

References 40 publications

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“…Ablation of peroxiredoxin (a nonenzymatic cellular antioxidant) in mice attenuated colitis by increasing Treg functions [133]. Most recently, lowered ROS levels were associated with chronic colitis in Ncf1/p47 phox -mutant mice, mediated by local accumulation of peroxynitrites, proinflammatory cytokines and lymphocytes and systemic immune deregulation, similar to in CGD patients [134]. These studies implicate an association of ROS level with T cell/Treg responsiveness.…”

Section: Protective Nature Of Rosmentioning

confidence: 99%

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

Khmaladze

Nandakumar

Holmdahl³

2015

Int Arch Allergy Immunol

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Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development.

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Section: Protective Nature Of Rosmentioning

confidence: 99%

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

Khmaladze

Nandakumar

Holmdahl³

2015

Int Arch Allergy Immunol

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“…However, p40 phox -deficient murine neutrophils display highly impaired ROS production upon stimulation with PMA or heat-killed S. aureus, but not SOZ (32). Moreover, gp91 phox -and p47 phox -KO mice (33)(34)(35) seem to have a less severe form of inflammatory colitis than do p40 phox -KO mice (36,37). The cellular and clinical overlap and differences between human p40 phox deficiency and classic CGD are largely unknown.…”

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confidence: 99%

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Geer¹,

Nieto-Patlán²,

Kuhns³

et al. 2018

Journal of Clinical Investigation

108

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Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40 phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40 phox -deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMAinduced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40 phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD. phox -deficient patient is compound heterozygous for a premature stop codon and a missense mutation in the PX domain that compromises binding to PI(3)P, which results in the impairment of neutrophil phagocytosis-induced oxidase activity (26). As in classic CGD neutrophils, intracellular oxidant production after stimulation with serum-opsonized zymosan (SOZ), IgG beads, or serumopsonized Staphylococcus aureus is impaired in the patient's neutrophils, and S. aureus killing is also defective (20,26,30). However, in this patient, unlike in classic CGD patients, the production of O 2 -by neutrophils in response to stimulation with PMA or formyl-methionyl-leucyl-phenylalanine (fMLF) is normal (26). The killing of S. aureus by neutrophils is also impaired in p40 phox deficiency and classic CGD are largely unknown. Here, we describe the characteristics of 24 patients from 12 families in 8 countries with biallelic mutations of NCF4. The Journal of Clinical Investigation R E S E A R C H A R T I C L E

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“…A possible involvement of ROS activity in Treg function was noted in models of autoimmune arthritis and colitis, where inhibition of ROS-producing enzyme system components like NCF-1 and NOX2 led to loss of Treg suppressor function, enhancement of effector responses, and aggravation of inflammatory lesions (49)(50)(51). Conceivably, the increase in ROS expression by Treg makes them more inhibitory against T effectors by inducing T cell death (52,53).…”

Section: Discussionmentioning

confidence: 99%

Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function

Varanasi

Reddy

Bhela

et al. 2017

J Virol

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Ocular infection with herpes simplex virus 1 (HSV-1) sets off an inflammatory reaction in the cornea which leads to both virus clearance and chronic lesions that are orchestrated by CD4 T cells. Approaches that enhance the function of regulatory T cells (Treg) and dampen effector T cells can be effective to limit stromal keratitis (SK) lesion severity. In this report, we explore the novel approach of inhibiting DNA methyltransferase activity using 5-azacytidine (Aza; a cytosine analog) to limit HSV-1-induced ocular lesions. We show that therapy begun after infection when virus was no longer actively replicating resulted in a pronounced reduction in lesion severity, with markedly diminished numbers of T cells and nonlymphoid inflammatory cells, along with reduced cytokine mediators. The remaining inflammatory reactions had a change in the ratio of CD4 Foxp3 ϩ Treg to effector Th1 CD4 T cells in ocular lesions and lymphoid tissues, with Treg becoming predominant over the effectors. In addition, compared to those from control mice, Treg from Aza-treated mice showed more suppressor activity in vitro and expressed higher levels of activation molecules. Additionally, cells induced in vitro in the presence of Aza showed epigenetic differences in the Treg-specific demethylated region (TSDR) of Foxp3 and were more stable when exposed to inflammatory cytokines. Our results show that therapy with Aza is an effective means of controlling a virusinduced inflammatory reaction and may act mainly by the effects on Treg.IMPORTANCE HSV-1 infection has been shown to initiate an inflammatory reaction in the cornea that leads to tissue damage and loss of vision. The inflammatory reaction is orchestrated by gamma interferon (IFN-␥)-secreting Th1 cells, and regulatory T cells play a protective role. Hence, novel therapeutics that can rebalance the ratio of regulatory T cells to effectors are a relevant issue. This study opens up a new avenue in treating HSV-induced SK lesions by increasing the stability and function of regulatory T cells using the DNA methyltransferase inhibitor 5-azacytidine (Aza). Aza increased the function of regulatory T cells, leading to enhanced suppressive activity and diminished lesions. Hence, therapy with Aza, which acts mainly by its effects on Treg, can be an effective means to control virus-induced inflammatory lesions.

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Deficient Production of Reactive Oxygen Species Leads to Severe Chronic DSS-Induced Colitis in Ncf1/p47phox-Mutant Mice

Cited by 27 publications

References 40 publications

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function

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