Ydens E, etal., J Neuroinflammation. 2015 Aug 8;12:143. doi: 10.1186/s12974-015-0367-8.
BACKGROUND: NOD-like receptors (Nlrs) are key regulators of immune responses during infection and autoimmunity. A subset of Nlrs assembles inflammasomes, molecular platforms that are activated in response to endogenous danger and microbial ligands and that control release of interleukin (IL)-1beta a
nd IL-18. However, their role in response to injury in the nervous system is less understood. METHODS: In this study, we investigated the expression profile of major inflammasome components in the peripheral nervous system (PNS) and explored the physiological role of different Nlrs upon acute nerve injury in mice. RESULTS: While in basal conditions, predominantly members of NOD-like receptor B (Nlrb) subfamily (NLR family, apoptosis inhibitory proteins (NAIPs)) and Nlrc subfamily (ICE-protease activating factor (IPAF)/NOD) are detected in the sciatic nerve, injury causes a shift towards expression of the Nlrp family. Sterile nerve injury also leads to an increase in expression of the Nlrb subfamily, while bacteria trigger expression of the Nlrc subfamily. Interestingly, loss of Nlrp6 led to strongly impaired nerve function upon nerve crush. Loss of the inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and effector caspase-1 and caspase-11 did not affect sciatic nerve function, suggesting that Nlrp6 contributed to recovery after peripheral nerve injury independently of inflammasomes. In line with this, we did not detect release of mature IL-1beta upon acute nerve injury despite potent induction of pro-IL-1beta and inflammasome components Nlrp3 and Nlrp1. However, Nlrp6 deficiency was associated with increased pro-inflammatory extracellular regulated MAP kinase (ERK) signaling, suggesting that hyperinflammation in the absence of Nlrp6 exacerbated peripheral nerve injury. CONCLUSIONS: Together, our observations suggest that Nlrp6 contributes to recovery from peripheral nerve injury by dampening inflammatory responses independently of IL-1beta and inflammasomes.
Birchenough GM, etal., Science. 2016 Jun 24;352(6293):1535-42. doi: 10.1126/science.aaf7419.
Innate immune signaling pathways contribute to the protection of host tissue when bacterially challenged. Colonic goblet cells are responsible for generating the two mucus layers that physically separate the luminal microbiota from the host epithelium. Analysis of colonic tissues from multiple mouse
strains allowed us to identify a "sentinel" goblet cell (senGC) localized to the colonic crypt entrance. This cell nonspecifically endocytoses and reacts to the TLR2/1, TLR4, and TLR5 ligands by activating the Nlrp6 inflammasome downstream of TLR- and MyD88-dependent Nox/Duox reactive oxygen species synthesis. This triggers calcium ion-dependent compound exocytosis of Muc2 mucin from the senGC and generates an intercellular gap junction signal; in turn, this signal induces Muc2 secretion from adjacent goblet cells in the upper crypt, which expels bacteria. Thus, senGCs guard and protect the colonic crypt from bacterial intruders that have penetrated the inner mucus layer.
Kempster SL, etal., Am J Physiol Gastrointest Liver Physiol. 2010 Nov 18.
The inflammasome is a multiprotein complex whose formation is triggered when a NOD-like receptor binds a pathogen ligand resulting in activated Caspase-1, which converts certain interleukins (IL1beta, IL-18 and IL-33) to their active forms. There is currently no information on regulation of this sys
tem around the time of birth. We employed transcript profiling of fetal rat intestinal and lung RNA at embryonic day 16 (E16) and E20 with out of sample validation using quantitative RT-PCR. Transcript profiling and quantitative RT-PCR demonstrated that transcripts of core components of the NOD-like receptor Nlrp6 inflammasome (Nlrp6, Pycard, Caspase-1) and one of its substrates, IL-18, were increased at E20, compared with E16 in fetal intestine and not lung. Immunohistochemistry demonstrated increased Pycard in intestinal epithelium. Western blotting demonstrated that IL-18 was undetectable at E16; clearly detectable at E20 in its inactive form and detectable postnatally in both its inactive and active form. Dramatic up-regulation of IL-18 was also observed in the fetal sheep jejunum in late gestation (p=0.006). Transcription factor binding analysis of the rat array data revealed an over-representation of nuclear transcription factor binding sites peroxisome proliferator-activated receptor gamma and retinoid X receptor alpha and chicken ovalbumin upstream promoter transcription factor 1 in the region 1000bp upstream of the transcription start site. Rosiglitazone, a PPAR-gamma agonist, more than doubled levels of NLRP6 mRNA in human intestinal epithelial (Caco2) cells. These observations provide the first evidence, to our knowledge, linking activity of PPAR-gamma to expression of a NOD-like receptor and adds to a growing body of evidence linking pattern recognition receptors of the innate immune system and intestinal colonization.
