Dietary fat differentially modulates the response of bone marrow-derived macrophages to TLR4 and NOD2 agonists.

Consumption of diets high in fat has been linked to the development of obesity and related metabolic complications. Such associations originate from the enhanced, chronic, low-grade inflammation mediated by macrophages in response to translocated bacteria, bacterial products, or dietary constituents such as fatty acids (FAs). Nucleotide-binding Oligomerization Domain 2 (NOD2) senses muramyl dipeptide (MDP), a component of bacterial peptidoglycan.

LMAN1 is a receptor for house dust mite allergens.

Development of therapies with the potential to change the allergic asthmatic disease course will require the discovery of targets that play a central role during the initiation of an allergic response, such as those involved in the process of allergen recognition. We use a receptor glycocapture technique to screen for house dust mite (HDM) receptors and identify LMAN1 as a candidate. We verify the ability of LMAN1 to directly bind HDM allergens and demonstrate that LMAN1 is expressed on the surface of dendritic cells (DCs) and airway epithelial cells (AECs) in vivo.

Intrarectal Xyloglucan Administration Reduces Disease Severity in the Dextran Sodium Sulfate Model of Mouse Colitis.

Background: The pathophysiology of inflammatory bowel diseases remains poorly understood and treatment remains suboptimal for many patients. We hypothesize that the inflammatory milieu secondarily prolongs the injury and attenuates healing. We propose primary or adjuvant therapy with biocompatible adhesives to restore a barrier to protect submucosal structures, particularly stem cells.

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2.

Exposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely Th2 and Th17 dominant, and a number of innate immune receptors have been identified that recognize HDM to initiate these responses. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic sensor of peptidoglycan, which is important for Th2 and Th17 polarization.

RIP2 promotes FcγR-mediated reactive oxygen species production.

Receptor-interacting protein 2 (RIP2) is a kinase that mediates signaling downstream of the bacterial peptidoglycan sensors NOD1 and NOD2. Genetic loss or pharmaceutical inhibition of RIP2 has been shown to be beneficial in multiple inflammatory disease models with the effects largely attributed to reducing proinflammatory signaling downstream of peptidoglycan recognition. However, given the widespread expression of this kinase and its reported interactions with numerous other proteins, it is possible that RIP2 may also function in roles outside of peptidoglycan sensing.

Frontline Science: RIP2 promotes house dust mite-induced allergic airway inflammation.

House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called "Atopic March." It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors.

In vivo inhibition of RIPK2 kinase alleviates inflammatory disease.

The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been associated with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacologic inhibition of RIPK2 an appealing strategy. In this work, we report the generation, identification, and evaluation of novel RIPK2 specific inhibitors.

Innate immune-directed NF-κB signaling requires site-specific NEMO ubiquitination.

While the I kappa kinase (IKK) scaffolding protein NF-κB essential modulator (NEMO) binds to polyubiquitin chains to transmit inflammatory signals, NEMO itself is also ubiquitinated in response to a variety of inflammatory agonists. Although there have been hints that polyubiquitination of NEMO is essential for avoiding inflammatory disorders, the in vivo physiologic role of NEMO ubiquitination is unknown. In this work, we knock in a NEMO allele in which two major inflammatory agonist-induced ubiquitination sites cannot be ubiquitinated.

A discrete ubiquitin-mediated network regulates the strength of NOD2 signaling.

Dysregulation of NOD2 signaling is implicated in the pathology of various inflammatory diseases, including Crohn's disease, asthma, and sarcoidosis, making signaling proteins downstream of NOD2 potential therapeutic targets. Inhibitor-of-apoptosis (IAP) proteins, particularly cIAP1, are essential mediators of NOD2 signaling, and in this work, we describe a molecular mechanism for cIAP1's regulation in the NOD2 signaling pathway. While cIAP1 promotes RIP2's tyrosine phosphorylation and subsequent NOD2 signaling, this positive regulation is countered by another E3 ubiquitin ligase, ITCH, through direct ubiquitination of cIAP1.

Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2-mediated disease.

The immune system is exquisitely balanced. It has the ability to effectively respond to and control infections while at the same time preventing inappropriate responses to self and environmental antigens. When this response goes awry, either through a failure to activate the immune response, or failure to terminate it, inflammatory pathology results.

Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cytokine responses.

Upon intracellular bacterial exposure, the Crohn's disease and sarcoidosis susceptibility protein NOD2 (nucleotide oligomerization domain protein 2) binds to the protein kinase RIP2 (receptor-interacting protein 2) to coordinate NF-κB (nuclear factor κ B)-mediated cytokine responses. While RIP2 clearly has kinase activity, the function of its kinase domain has been enigmatic. Although originally classified as a serine-threonine kinase based on homology scans, we find that RIP2 also has tyrosine kinase activity.

Encephalitogenicity of complete Freund's adjuvant relative to CpG is linked to induction of Th17 cells.

For decades, CFA has been the classic adjuvant for the induction of experimental autoimmune encephalomyelitis (EAE). Its encephalitogenic activity has been originally linked to the induction of Th1 responses. CpG, which is also a potent Th1 inducer, has been suggested by some studies to be comparably encephalitogenic.

Dissociated induction of cytotoxicity and DTH by CFA and CpG.

Vaccinations typically rely on immunization with live virus for eliciting protective CD8 T cell immunity. There is increasing interest to use subunit vaccination strategies to achieve such responses. Complete Freund's adjuvant (CFA) and unmethylated cytosine-guanine dinucleotide containing DNA are considered some of the most potent adjuvants for eliciting immunity.

Th1 responses to beta-amyloid in young humans convert to regulatory IL-10 responses in Down syndrome and Alzheimer's disease.

A beta(1-42)-specific antibodies and T-cell proliferation point to the existence of a memory response to A beta(1-42) in humans. Using ELISPOT, we studied A beta(1-42)-specific T cells in individuals of various ages, and in subjects with Trisomy 21 or Alzheimer's disease. We show for the first time that A beta(1-42)-specific Th1-type T-cell memory is present in young humans, producing high levels of IFN-gamma and IL-2.