MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function

0472035 - ÚMG 2017 RIV US eng J - Článek v odborném periodiku
Brauer, Rena - Turečková, Jolana - Kanchev, Ivan - Khoylou, M. - Škarda, J. - Procházka, Jan - Špoutil, František - Beck, Inken - Žbodáková, Olga - Kašpárek, Petr - Kořínek, Vladimír - Chalupský, Karel - Karhu, T. - Herzig, K.H. - Hajduch, M. - Gregor, Martin - Sedláček, Radislav
MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function.
Mucosal Immunology. Roč. 9, č. 4 (2016), s. 974-985. ISSN 1933-0219. E-ISSN 1935-3456
Grant CEP: GA ČR GAP302/11/2048; GA ČR GAP303/10/2044; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:68378050
Klíčová slova: human matrix-metalloproteinase * inflammatory-bowel-disease * differential expression * chemokine fractalkine * epithelial-cells * myeloid cells * in-vivo * mice * tissue * identification
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 7.478, rok: 2016

Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of proinflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-)mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
Trvalý link: http://hdl.handle.net/11104/0269379