Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer.

Expression of Toll-interacting protein (Tollip), a potent TLR modulator, decreases in patients with inflammatory bowel diseases (IBD), whereas Tollip <sup>-/-</sup> mice are susceptible to colitis. Tollip expression was shown to be reduced in sporadic adenoma . In contrast, we found variable Tollip expression in patients with colitis-associated adenomas. In Tollip <sup>-/-</sup> mice challenged to develop colitis-associated cancer (CAC), tumor formation was significantly reduced owing to decreased mucosal proliferative and apoptotic indexes. This protection was associated with blunt inflammatory responses without significant changes in microbial composition. mRNA expression of Cd62l and Ccr5 homing receptors was reduced in colons of untreated Tollip <sup>-/-</sup> mice, whereas CD62L <sup>+</sup> CD8 <sup>+</sup> T cells accumulated in the periphery. In Tollip-deficient adenomas Ctla-4 mRNA expression and tumor-infiltrating CD4 <sup>+</sup> Foxp3 <sup>+</sup> regulatory T cell (Treg) were decreased. Our data show that protection from CAC in Tollip-deficient mice is associated with defects in lymphocyte accumulation and composition in colitis-associated adenomas

Tollip, an early regulator of the acute inflammatory response in the substantia nigra.

Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease. We first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice. We report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2'-deoxyguanosine and nitrotyrosine immunostaining, respectively. Altogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson's disease, Tollip may be a potential target for neuroprotection

Managing Performance Throughout Periods of Travel

Understanding the impact of travel on physical performance is an increasing area of interest for the strength and conditioning practitioner. Previous research surrounding the effect of travel on the physiology of an athlete has focused on sleep. Of concern to coaches and athletes are strategies to help attenuate any detrimental impact of travel on subsequent performance. The aim of this article is to provide informative practical guidelines for before, during, and after travel that can be implemented by coaches and athletes. The key coping strategies addressed include timed light exposure; managing sleep deprivation and nutritional recommendations

Mouse (Tollip) Immuno Profiling Panel (NS_Immunology_MM_C2269)

Aim: Analysis of differential expression for dataset genes in colon of Tollip -/- mice versus Tollip +/+ wt in steady state condition or upon colitis-associated cancer.Groups: A) For baseline “comparisons to non-treated Tollip+/+” the following comparisons were performed: treated Tollip-/- vs non-treated Tollip+/+, non-treated Tollip-/- vs non-treated Tollip+/+ and treated Tollip+/+ vs non-treated Tollip+/+. B) For the baseline “comparisons to treated Tollip+/+” the following comparisons were performed: treated Tollip-/- vs treated Tollip+/+, non-treated Tollip-/- vs treated Tollip+/+. C) For the baseline “comparisons to non-treated Tollip-/-” the following comparisons were performed: treated Tollip-/- vs non-treated Tollip-/-

Mouse (Tollip) Immuno Profiling Panel (NS_Immunology_MM_C2269)

Aim: Analysis of differential expression for dataset genes in colon of Tollip -/- mice versus Tollip +/+ wt in steady state condition or upon colitis-associated cancer.Groups: A) For baseline “comparisons to non-treated Tollip+/+” the following comparisons were performed: treated Tollip-/- vs non-treated Tollip+/+, non-treated Tollip-/- vs non-treated Tollip+/+ and treated Tollip+/+ vs non-treated Tollip+/+. B) For the baseline “comparisons to treated Tollip+/+” the following comparisons were performed: treated Tollip-/- vs treated Tollip+/+, non-treated Tollip-/- vs treated Tollip+/+. C) For the baseline “comparisons to non-treated Tollip-/-” the following comparisons were performed: treated Tollip-/- vs non-treated Tollip-/-.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Preventing Overheating: Tight Control of Gut Innate Immunity in Health and Disease.

Innate immune responses are key to maintain adequate host-microbial interactions. However, those signals are needed to efficiently trigger rapid and targeted antimicrobial responses in case of pathogen encounter. Several molecules have evolved to regulate intensity and coordinate signaling to avoid detrimental consequences to the host. Regulation can occur at the cell surface, within the cytoplasm, and at the transcriptional level. Innate immune regulation seems to be equally important than stimulation, as disruption of immunoregulatory molecules modulates the risk for several diseases. This is the case for colitis and inflammatory bowel disease but also colorectal cancer and intestinal infections. In this review, we recapitulate the molecular mechanisms underlying regulation of innate immune signals and mention their implications in several disease states including inflammatory bowel disease

Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung

Short-chain fatty acids (SCFAs) are metabolites that are produced following microbial fermentation of dietary fibre and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of haematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to enhanced mobilization of neutrophils to the lungs as a result of increased CXCR2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced expression of nicotinamide adenine dinucleotide phosphate (NADPH), oxidase complex components required for reactive oxygen species (ROS) production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection

Additional file 4: Figure S4. of Tollip, an early regulator of the acute inflammatory response in the substantia nigra

No induction of iNOS 6 h after PBS injection in the midbrain of Tollip KO mice. A representative iNOS and NeuN immunostaining in the midbrain in contralateral and ipsilateral side of the PBS (1 μL) injection, in Tollip KO mice. Magnification = ×40. Scale bar = 30 μm. (TIF 740 kb