586 research outputs found
Nutrient Supplementation Habits of Active Duty Military Members
Housing, Interior Design and Consumer Studie
Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis
Background: Inflammatory bowel diseases,
encompassing Crohn’s disease and ulcerative colitis, are
characterised by persistent leucocyte tissue infiltration
leading to perpetuation of an inappropriate inflammatory
cascade. The neuronal guidance molecule netrin-1 has
recently been implicated in the orchestration of
leucocyte trafficking during acute inflammation. We
therefore hypothesised that netrin-1 could modulate
leucocyte infiltration and disease activity in a model of
inflammatory bowel disease.
Design: DSS-colitis was performed in mice with partial
genetic netrin-1 deficiency (Ntn-1+/- mice) or wild-type
mice treated with exogenous netrin-1 via osmotic pump
to examine the role of endogenous and therapeutically
administered netrin-1. These studies were supported by
in vitro models of transepithelial migration and intestinal
epithelial barrier function.
Results: Consistent with our hypothesis, we observed
induction of netrin-1 during intestinal inflammation in vitro
or in mice exposed to experimental colitis. Moreover,
mice with partial netrin-1 deficiency demonstrated an
exacerbated course of DSS-colitis compared to littermate
controls, with enhanced weight loss and colonic
shortening. Conversely, mice treated with exogenous
mouse netrin-1 experienced attenuated disease severity.
Importantly, permeability studies and quantitative
assessment of apoptosis reveal that netrin-1 signalling
events do not alter mucosal permeability or intestinal
epithelial cell apoptosis. In vivo studies of leucocyte
transmigration demonstrate suppression of neutrophil
trafficking as a key function mediated by endogenous or
exogenously administered netrin-1. Finally, genetic
studies implicate the A2B adenosine receptor in
netrin-1-mediated protection during DSS-colitis.
Conclusions: The present study identifies a previously
unrecognised role for netrin-1 in attenuating experimental
colitis through limitation of neutrophil trafficking
Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu
Mucosal Associated Invariant T cells are a population of “innate” T cells, which express
the invariant T cell receptor (TCR) a chain Va7.2-Ja33 and are capable of robust rapid
cytokine secretion, producing a milieu of cytokines including IFN-g and IL-17. MAIT
cells have been reported in multiple human tissues including the gut, periphery and
skin. On-going research has highlighted their involvement in numerous inflammatory
diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis
Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in
painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been
implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is
currently unknown. In this study we show for the first time, that MAIT cells are altered
in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17
cytokine bias. We show that CCL20 expression is elevated in lesions of patients with
H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT
cells can accumulate in the lesionsfrom patients with H.S. when compared to adjacent
skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation
of dermal fibroblasts, promoting the expression of chemotactic signals including
CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt
robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively
our data detailsIL-17 producing MAIT cells as a novel player in the pathogenesis of H.S
and highlights the potential of RORyt inhibition as a novel therapeutic strategy
Tissue-Resident NK Cells Mediate Ischemic Kidney Injury and Are Not Depleted by Anti-Asialo-GM1 Antibody
NK cells are innate lymphoid cells important for immune surveillance, identifying and responding to stress, infection, and/or
transformation. Whereas conventional NK (cNK) cells circulate systemically, many NK cells reside in tissues where they appear to
be poised to locally regulate tissue function. In the present study, we tested the contribution of tissue-resident NK (trNK) cells to
tissue homeostasis by studying ischemic injury in the mouse kidney. Parabiosis experiments demonstrate that the kidney contains
a significant fraction of trNK cells under homeostatic conditions. Kidney trNK cells developed independent of NFIL3 and T-bet,
and they expressed a distinct cell surface phenotype as compared with cNK cells. Among these, trNK cells had reduced asialoGM1 (AsGM1) expression relative to cNK cells, a phenotype observed in trNK cells across multiple organs and mouse strains.
Strikingly, anti–AsGM1 Ab treatment, commonly used as an NK cell–depleting regimen, resulted in a robust and selective
depletion of cNKs, leaving trNKs largely intact. Using this differential depletion, we tested the relative contribution of cNK
and trNK cells in ischemic kidney injury. Whereas anti–NK1.1 Ab effectively depleted both trNK and cNK cells and protected
against ischemic/reperfusion injury, anti–AsGM1 Ab preferentially depleted cNK cells and failed to protect against injury. These
data demonstrate unanticipated specificity of anti–AsGM1 Ab depletion on NK cell subsets and reveal a new approach to study the
contributions of cNK and trNK cells in vivo. In total, these data demonstrate that trNK cells play a key role in modulating local
responses to ischemic tissue injury in the kidney and potentially other organs
SMAD Signaling in the Airways of Healthy Rhesus Macaques versus Rhesus Macaques with Asthma Highlights a Relationship Between Inflammation and Bone Morphogenetic Proteins
Bone morphogenetic protein (BMP) signaling is important for
correct lung morphogenesis, and there is evidence of BMP signaling
reactivation in lung diseases. However, little is known about BMP
signaling patterns in healthy airway homeostasis and inflammatory
airway disease and during epithelial repair. In this study, a rhesus
macaque (Macaca mulatta) model of allergic airway disease was used
to investigate BMP signaling throughout the airways in health,
disease, and regeneration. Stereologic quantification of
immunofluorescent images was used to determine the expression of
BMP receptor (BMPR) Ia and phosphorylated SMAD (pSMAD)
1/5/8 in the airway epithelium. A pSMAD 1/5/8 expression gradient
was found along the airways of healthy juvenile rhesus macaques
(n = 3, P , 0.005). Membrane-localized BMPRIa expression was also
present in the epithelium of the healthy animals. After exposure to
house dust mite allergen and ozone, significant down-regulation of
nuclear pSMAD 1/5/8 occurs in the epithelium. When the animals
were provided with a recovery period in filtered air, proliferating cell
nuclear antigen, pSMAD 1/5/8, and membrane-localized BMPRIa
expression were significantly increased in the epithelium of
conducting airways (P , 0.005). Furthermore, in the asthmatic
airways, altered BMPRIa localization was evident. Because of the
elevated eosinophil presence in these airways, we investigated the
effect of eosinophil-derived proteins on BMPRIa trafficking in
epithelial cells. Eosinophil-derived proteins (eosinophil-derived
neurotoxin, eosinophil peroxidase, and major basic protein) induced
transient nuclear translocation of membrane-bound BMPRIa. This
work mapping SMAD signaling in the airways of nonhuman
primates highlights a potential mechanistic relationship between
inflammatory mediators and BMP signaling and provides evidence
that basal expression of the BMP signaling pathway may be
important for maintaining healthy airways
Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis
Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence
implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosinemediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine
receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies
and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b / mice experienced a
significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial
barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2bfl/flVeCadCre þ ) or
intestinal epithelia (Adora2bfl/flVillinCre þ ) revealed a selective role for epithelial Adora2b signaling in attenuating colonic
inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies
highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier
repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist
(BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling
provides protection during intestinal inflammation via enhancing mucosal barrier responses
Autophagy mediates epithelial cytoprotection in Eosinophilic Oesophagitis
Objective—The influence of eosinophilic oesophagitis (EoE)-associated inflammation upon oesophageal epithelial biology remains poorly understood. We investigated the functional role of autophagy in oesophageal epithelial cells (keratinocytes) exposed to the inflammatory EoE milieu.
Design—Functional consequences of genetic or pharmacological autophagy inhibition were assessed in endoscopic oesophageal biopsies, human oesophageal keratinocytes, single cell-derived ex vivo murine oesophageal organoids as well as a murine model recapitulating EoE-like inflammation and basal cell hyperplasia. Gene expression, morphological and functional characterization of autophagy and oxidative stress were performed by transmission electron microscopy, immunostaining, immunoblotting, live cell imaging and flow cytometry.
Results—EoE-relevant inflammatory conditions promoted autophagy and basal cell hyperplasia in three independent murine EoE models and oesophageal organoids. Inhibition of autophagic flux via chloroquine treatment augmented basal cell hyperplasia in these model systems. Oesophageal keratinocytes stimulated with EoE-relevant cytokines, including tumor necrosis factor-α and interleukin-13 exhibited activation of autophagic flux in a reactive oxygen species-dependent manner. Autophagy inhibition via chloroquine treatment or depletion of Beclin-1 or ATG-7, augmented oxidative stress induced by EoE-relevant stimuli in murine EoE, oesophageal organoids and human oesophageal keratinocytes. Oesophageal epithelia of pediatric EoE patients with active inflammation displayed increased autophagic vesicle content compared to normal and EoE remission subjects. Functional flow cytometric analysis revealed autophagic flux in human oesophageal biopsies.Conclusions—Our findings reveal for the first time that autophagy may function as a cytoprotective mechanism to maintain epithelial redox balance and homeostasis under EoE inflammation-associated stress, providing mechanistic insights into the role of autophagy in EoE pathogenesis
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