Monica Yabal

Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan^1–3. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 2⁴ (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function⁵. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway⁶. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP—but not unmodified MDP—constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.

In XIAP deficiency, ileitis is driven by TNFR1- and TNFR2-dependent targeting of TLR5-expressing Paneth and dendritic cells.

The inhibitor of apoptosis proteins (IAPs) are best known for their ability to regulate cell survival and death processes. However, in addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division. Many of these IAP functions are non-redundant even though they are based on the same molecular mechanism of action. These distinct functions of IAPs derive from their capacity to target specific substrates for ubiquitination and/or proteolytic cleavage. The unique functions of IAPs also derives from their unique cellular localizations, cell type and tissue-specific expression patterns. The diverse roles of IAPs are reflected by the fact that in humans the IAP family comprises eight distinct members. Genetic evidence from human pathologies also attests to the non-redundant functions of the IAPs since very diverse diseases arise upon aberrant IAP expression. In this review, we give an overview of the known mechanisms of action of the various IAPs, and focus on their specific roles in mediating innate immunity. We also look at the distinct phenotypes related to the dysregulation of the IAPs, and the human pathologies associated with each human IAP.

Summary: Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop inxiap^−/−macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation lead to cell death inxiap^−/−myeloid cells, particularly in the absence the RING domain. RIPK1/TAK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death independent of necroptosis. TNFR2-specific activation lead to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of up-regulation of NLRP3 and caspase-11. Activation and up-regulation of the canonical inflammasome was mediated by RIPK1 kinase activity and ROS production. While both RIPK1 kinase activity and ROS production reduced cell death as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports, targeting TNFR2 specifically to reduce IL-18 release in XIAP deficient (XLP-2) patients.