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Title: Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1/p47phox-mutant mice
Authors: Rodrigues-Sousa, Tiago 
Ladeirinha, Ana Filipa Ferreira 
Santiago, Ana Raquel 
Carvalheiro, Helena 
Raposo, Bruno
Alarcão, Ana 
Cabrita, António 
Holmdahl, Rikard
Carvalho, Lina 
Carneiro, M. Margarida Souto 
Issue Date: 2014
Publisher: Public Library of Science
Project: SFRH/BD/60467/2009 
Marie Curie grant PERGGA- 2008-239422 
Swedish Research Council 
EU FP7 project Neurinox 
Serial title, monograph or event: PLoS ONE
Volume: 9
Issue: 5
Abstract: Background: Colitis is a common clinical complication in chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired oxidative burst. Existing experimental data from NADPH-oxidase knockout mice propose contradictory roles for the involvement of reactive oxygen species in colitis chronicity and severity. Since genetically controlled mice with a point-mutation in the Ncf1 gene are susceptible to chronic inflammation and autoimmunity, we tested whether they presented increased predisposition to develop chronic colitis. Methods: Colitis was induced in Ncf1-mutant and wild-type mice by a 1st 7-days cycle of dextran sulfate sodium (DSS), intercalated by a 7-days resting period followed by a 2nd 7-days DSS-cycle. Cytokines were quantified locally in the colon inflammatory infiltrates and in the serum. Leukocyte infiltration and morphological alterations of the colon mucosa were assessed by immunohistochemistry. Results: Clinical scores demonstrated a more severe colitis in Ncf1-mutant mice than controls, with no recovery during the resting period and a severe chronic colitis after the 2nd cycle, confirmed by histopathology and presence of infiltrating neutrophils, macrophages, plasmocytes and lymphocytes in the colon. Severe colitis was mediated by increased local expression of cytokines (IL-6, IL-10, TNF-a, IFN-c and IL-17A) and phosphorylation of Leucine-rich repeat kinase 2 (LRRK2). Serological cytokine titers of those inflammatory cytokines were more elevated in Ncf1-mutant than control mice, and were accompanied by systemic changes in functional subsets of monocytes, CD4+T and B cells. Conclusion: This suggests that an ineffective oxidative burst leads to severe chronic colitis through local accumulation of peroxynitrites, pro-inflammatory cytokines and lymphocytes and systemic immune deregulation similar to CGD.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0097532
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais
I&D IBILI - Artigos em Revistas Internacionais

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