IL-1b promotes pathogenic type 17 responses from both innate and adaptive leukocytes in the gut

Este post foi escrito pelo Dr. Kevin Maloy, pesquisador e professor da Universidade de Oxford. O Dr. Maloy trabalhou com grandes cientistas como Dr. Rolf Zinkernagel e Dr. Fiona Powrie, e hoje lidera seu próprio grupo no estudo das interações patógeno-hospedeiro na doença crônica intestinal. Ele visitou o Brasil no começo deste ano, esteve na Fiocruz e UFMG, onde apresentou seus dados mais recentes, que foram publicados este mês no Journal of Experimental Medicine. Para os que não tiveram a oportunidade de assistir ao seminário, ou ler o artigo, aqui está o comentário escrito por ele para o nosso SBlogI. Dr. Kevin tem a intenção de voltar ao Brasil mais vezes para a realização de colaborações e quem sabe contribuir mais vezes para o nosso blog.

Boa leitura!

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the intestine that are associated with aberrant immune responses to the intestinal bacterial microflora. Better characterization of pathogenic pathways involved in IBD has led to the development of novel biological therapies, such as reagents that target TNF. Studies in IBD patients have associated high IL-1b levels with intestinal pathology, but the mechanisms through which IL-1b might drive intestinal inflammation were not known.

In this study, we employed mouse models of IBD to better define the role of IL-1b in intestinal inflammation. Using a model in which intestinal pathology is mediated by innate immune responses to an intestinal bacterial infection we found that treatment with an anti-IL-1b antibody led to significant attenuation of intestinal inflammation. We found that IL-1b blockade resulted in decreased granulocyte recruitment to the intestine and also reduced the accumulation and activation of innate lymphoid cells (ILC), a recently discovered type of innate leukocyte that can contribute to inflammation in the gut. Using a different IBD model in which disease is driven by CD4⁺ T cells we found that IL-1R signalling in T cells played a key role in T-cell mediated intestinal pathology by promoting their accumulation and survival in the gut. Our experiments also revealed synergies between IL-1b and IL-23 in driving pathogenic type 17 cytokine responses. We found that IL-1b potentiated IL-17 secretion by intestinal ILC by enhancing their expression of IL-23R. In contrast, IL-23 signals led to increased expression of IL-1R by CD4⁺ Th17 cells.

Taken together, our studies show that IL-1b promotes intestinal inflammation by acting together with IL-23 to drive innate and adaptive inflammatory responses in the gut (Figure1).  They suggest that targeting of the IL-1b pathway may be a useful therapeutic approach in IBD and in other immune pathologies associated with the IL-23/Th17 axis.

Ref: Coccia, M. et al. J. Exp. Med. (2012) DOI: 10.1084/jem.20111453.