Molecular mechanism of dendritic cell semimaturation and role in maintenance of intestinal homeostasis
Zusammenfassung der Projektergebnisse
We showed that different intracellular mechanisms contribute to the B. vulgatus induced differentiation of dendritic cells to semimature dendritic cells. This mechanisms proofed to be relevant in the ex vivo model system of BMDC as well as in mouse models in vivo. From our analyses focusing on IκBζ we conclude that IκBζ is essential for the differentiation of DC to a smDC effector state which seems to favor immune homoeostasis and prevents overwhelming inflammatory host responses. Thus IκBζ contributes significantly to the intestinal mucosal immune balance mediated most likely by myeloid cells. We suggest that in future IκBζ might be a potential cellular target for novel therapeutic anti-inflammatory strategies. Our analyses addressing CTSS showed that B. vulgatus induces DC semi-maturation via regulation of CTSS activity. This prevents from pathological reactions of the immune system and therefore contributes to the maintenance of the intestinal homeostasis. This could be underlined by the observation that B. vulgatus protects Rag1-/- mice from colitis induction by inducing DC semi-maturation and inhibition of CTSS secretion. This makes B. vulgatus a promising candidate for the treatment also of other AID, not only IBD. We think that B. vulgatus might be an even better tool than a chemical inhibitor to treat CTSS-associated AID since (i) it is easily administrable, (ii) it does not completely suppress physiological functions of CTSS but only suppresses pathological activities and (iii) it acts as a commensal symbiont of the body. It does not influence a normal immune response due to acute infections but strongly inhibits pathological gut microbiota associated immune responses. Therefore severe side effects of CTSS inhibition should not occur and could not be observed in the used mouse model, another advantage over a chemical inhibitor.
