Innate Immunity

Inflammable Mucus

Sci. Signal.  18 Mar 2014:
Vol. 7, Issue 317, pp. ec71
DOI: 10.1126/scisignal.2005282

Mice deficient for NLRP6 (NOD-like receptor family pyrin domain–containing 6) have disrupted intestinal homeostasis and increased susceptibility to intestinal infection. NLRP6 is a component of the cytoplasmic inflammasome protein complex, which is typically found in myeloid cells and promotes innate immune responses to pathogen- and damage-associated molecular patterns. Wlodarska et al. found that NLRP6 inflammasomes are required in intestinal epithelial cells for mucus production. Compared with wild-type mice, Nlrp6–/– mice inoculated with Citrobacter rodentium had more persistent and severe colonic infections. Likewise, mice deficient for other components of the inflammasome, including Asc–/– as well as Caspase-1–/– and Caspase-11–/– (Casp1/11–/–) mice, also failed to resolve colonic infections. This effect did not appear to be the result of a primary defect in immune activation. Instead, the authors found that Nlrp6 was expressed in the goblet cells, which secrete mucus, and Nlrp6–/–, Asc–/–, and Casp1/11–/– mice had goblet cell hyperplasia and less intestinal mucus. In Nlrp6–/– and Asc–/– mice, mucin-containing granules were present in the intestinal lumen rather than inside goblet cells, suggesting that goblet cell granule exocytosis was disrupted. The goblet cells of Nlrp6–/–, Asc–/–, and Casp1/11–/– mice had decreased lipidation of LC3 (microtubule-associated protein 1-light chain 3) and increased abundance of p62 (also known as sequestosome 1), indicating that autophagy was impaired in these cells. Mice with heterozygous deletion of autophagy gene 5, which is required for autophagy, had less intestinal mucus, goblet cell hyperplasia, and disrupted granule exocytosis. Thus, inflammasome signaling in intestinal goblet cells stimulates autophagy required for mucus production and resistance to infection.

M. Wlodarska, C. A. Thaiss, R. Nowarski, J. Henao-Mejia, J.-P. Zhang, E. M. Brown, G. Frankel, M. Levy, M. N. Katz, W. M. Philbrick, E. Elinav, B. B. Finlay, R. A. Flavell, NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014). [Abstract]