Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1/p47phox-mutant mice

• Autor(a) principal: Rodrigues-Sousa, Tiago
• Data de Publicação: 2014
• Outros Autores: Ladeirinha, Ana Filipa Ferreira, Santiago, Ana Raquel, Carvalheiro, Helena, Raposo, Bruno, Alarcão, Ana, Cabrita, António, Holmdahl, Rikard, Carvalho, Lina, Carneiro, M. Margarida Souto
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/109646; https://doi.org/10.1371/journal.pone.0097532
• topic: Animals; Chronic Disease; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammation Mediators; Intestinal Mucosa; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Leukocytes; Male; Mice; Mice, Knockout; NADPH Oxidases; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Mutation

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.