RÉSUMÉ
As a potent effector of innate immunity, the complement system has been shown to be involved in the pathogenesis of inflammatory bowel disease (IBD). However, the role of the membrane attack complex (MAC) in the development of IBD is still largely unknown. Here, we used C6-deficient mice in which MAC formation was blocked due to the absence of C6 to develop an acute colitis model by the administration of dextran sulfate sodium (DSS). The results showed that DSS-induced colitis was aggravated in C6-deficient mice compared with wild-type (WT) mice, as represented by the markedly greater weight loss, higher disease activity index (DAI), shortened colon length, more severe histological injury with increased epithelial ulcerations, and massively increased infiltration of leukocytes accompanied by much higher myeloperoxidase (MPO) levels in local inflammatory colonic sites. In addition, the DSS-induced colitis in C6-deficient mice could be significantly ameliorated by the exogenous C6 from WT sera. Furthermore, the significantly enhanced production of pro-inflammatory mediators, including IL-1ß, IL-6, CXCL-1, CCL-3, TGF-ß1 and IL-17F, was also observed in C6-deficient mice. Unexpectedly, the aggravated colitis in C6-deficient mice may be not due to the increase of lipopolysaccharide (LPS) levels in serum. Overall, we demonstrated that MAC exerts a protective role in acute colitis, strongly highlighting the host defense function of the complement system.
Sujet(s)
Colite/étiologie , Complément C6/déficit , Sulfate dextran/effets indésirables , Prédisposition aux maladies , Déficits immunitaires/complications , Déficits immunitaires/immunologie , Animaux , Colite/traitement médicamenteux , Colite/métabolisme , Colite/anatomopathologie , Complément C6/administration et posologie , Complément C6/immunologie , Complexe d'attaque membranaire du complément/immunologie , Complexe d'attaque membranaire du complément/métabolisme , Protéines du système du complément/immunologie , Protéines du système du complément/métabolisme , Cytokines/métabolisme , Modèles animaux de maladie humaine , Déficits héréditaires en complément , Humains , Médiateurs de l'inflammation/métabolisme , Maladies inflammatoires intestinales/immunologie , Maladies inflammatoires intestinales/métabolisme , Maladies inflammatoires intestinales/anatomopathologie , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Muqueuse intestinale/anatomopathologie , Leucocytes/immunologie , Leucocytes/métabolisme , Leucocytes/anatomopathologie , Souris , Souris knockoutRÉSUMÉ
The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.