Epithelia Control Gut Inflammation

Science's STKE  03 Apr 2007:
Vol. 2007, Issue 380, pp. tw114
DOI: 10.1126/stke.3802007tw114

The intestinal epithelial cells (IECs) provide a crucial barrier function preventing infection. Now these cells also are recognized as key instructors of inflammatory responses. Zaph et al. and Nenci et al. both used IEC-targeted gene knockouts in mice to show that nuclear factor κB (NF-κB) signaling in the IECs was essential for controlling infection and inflammatory responses. Zaph et al. knocked out IKKβ (IkkbΔIEC mice) and Nenci et al. knocked out IKKγ (also known as NEMO) (NEMOIEC-KO mice) or both IKKα and IKKβ (IKK1/2IEC-KO); these kinases are involved in NF-κB activation. Zaph et al. studied the mouse response to Trichuris muris infection as a model of human nematode infections. Trichuris infection triggered NF-κB activation in the IECs of wild-type mice, and these mice developed a T helper 2 (TH2) response; produced interleukin (IL)-4, -5, and -13; and cleared the infection. In contrast, the type 2 immune response of the IkkbΔIEC mice was impaired and the mice failed to clear the infection and developed severe intestinal inflammation with infiltration of lymphocytes, ulceration, and ultimately septicemia. This appeared to be due to decreased expression of the RNA of thymic stromal lymphopoietin (TSLP), which is encoded by an NF-κB-regulated gene. TSLP limits dendritic cell proinflammatory cytokine production, limits dendritic cell signals that trigger TH1 differentiation, and promotes dendritic cell signals that trigger TH2 cell differentiation. The NEMOIEC-KO and IKK1/2IEC-KO mice studied by Nenci et al. exhibited a more severe phenotype with spontaneous formation of chronic severe intestinal inflammation. This was due to the complete abrogation of NF-κB signaling in these two knockout mice strains, whereas loss of IKKβ or IKKα function alone impairs but does not eliminate NF-κB signaling. The colitis that the NEMOIEC-KO mice developed was prevented if the mice were also deficient in MyD88, which is an adaptor important for Toll-like receptor (TLR) signaling triggered by pathogens such as intestinal bacteria. Colitis was also prevented in the NEMOIEC-KO if the mice were deficient for tumor necrosis factor-α (TNF-α) receptors. This was consistent with the observation that NEMO-deficient cells are more sensitive to apoptosis caused by TNF-α. Together these two articles clearly show that the NF-κB signaling in IECs plays a crucial role in controlling inflammatory responses and fighting infection in the gut.

C. Zaph, A. E. Troy, B. C. Taylor, L. D. Berman-Booty, K. J. Guild, Y. Du, E. A. Yost, A. D. Gruber, M. J. May, F. R. Greten, L. Eckmann, M. Karin, D. Artis, Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552-556 (2007). [PubMed]

A. Nenci, C. Becker, A. Wullaert, R. Gareus, G. van Loo, S. Danese, M. Huth, A. Nikolaev, C. Neufert, B. Madison, D. Gumucio, M. F. Neurath, M. Pasparakis, Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561 (2007). [PubMed]