Tissue-Expressed B7-H1 Critically Controls Intestinal Inflammation

Scandiuzzi, Lisa; Ghosh, Kaya; Hofmeyer, Kimberly A.; Abadi, Yael M.; Lázár‐Molnár, Eszter; Lin, Elaine Y.; Liu, Qiang; Jeon, Hyungjun; Almo, Steven C.; Chen, Lieping; Nathenson, Stanley G.; Zang, Xingxing

doi:10.1016/j.celrep.2014.01.020

Cited by 59 publications

(70 citation statements)

References 31 publications

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“…This association supports the notion that up-regulation of PD-L1 in the gut has a potential role in human septic condition. In keeping with several other studies, increased PD-L1 expression is associated with intestinal dysfunction in patients with IBD (13,15,18).…”

Section: Junction Integritysupporting

confidence: 70%

“…2A). Studies showed that PD-L1 was detectable in human gastric epithelial cells (17) and colonic epithelial cells (13,15,18). We confirmed that PD-L1 mRNA and protein were constitutively expressed in freshly isolated small intestinal epithelial cells (IECs) from naïve WT mice ( Supplementary Fig.1).…”

Section: Sepsis Increases Pd-l1 Expression In the Mouse Intestinesupporting

confidence: 63%

“…Additionally, studies have indicated that PD-L1 is not only expressed, but also involved in intestinal mucosal inflammation and regulates gut immune tolerance (15,16). PD-L1 has been reported to be expressed on colonic and gastric epithelial cells, and in select situations, it contributes to the interaction between epithelial cells and lymphocytes (15,17,18). Intestinal epithelium is the key component of intestinal barrier, which separates bacteria and toxic substances in the gut from the sub-mucosal lymphoid tissue and maintaining intestinal immune homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

Chung

Chen

et al. 2016

Mol Med

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Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, co-inhibitory molecule, programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it isn't known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability, tissue cytokine levels were assessed. Subsequently, septic or non-septic patient colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 I a blinded fashion. Finally, human Caco2 cells were used for in vitro studies.The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly upregulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed an increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability, tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared to WT after sepsis. Comparatively, while Caco2 cell monolayers responded to inflammatory cytokine stimulation also with elevated PD-L1 expression, increased monolayer permeability and altering/decreasing monolayer tight junction protein morphology/expression; these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of ICE PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction.

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Section: Junction Integritysupporting

confidence: 70%

Section: Sepsis Increases Pd-l1 Expression In the Mouse Intestinesupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

Chung

Chen

et al. 2016

Mol Med

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“…PD-L1 is immuno-inhibitory and is normally up-regulated during inflammation to help minimise tissue damage 29 . Failure to express PD-L1 in the intestine enhances the risk of inflammation 32,33 but especially so when non-self antigen is being expressed 34 . Thus, not only might the nanomineral pathway ensure that luminal antigen and peptidoglycan reach sub-epithelial immune cells without enzymatic degradation en route but, additionally, it could ensure that the very cells in receipt of exogenous non-self antigens are also the ones expressing PD-L1.…”

Section: Discussionmentioning

confidence: 99%

An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells

et al. 2015

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In humans and other mammals, it is known that calcium and phosphate ions are secreted from the distal small intestine into the lumen. However, why this secretion occurs is unclear. Here, we show that the process leads to the formation of amorphous magnesium-substituted calcium phosphate nanoparticles that trap soluble macromolecules, such as bacterial peptidoglycan and orally-fed protein antigens, in the lumen and transport them to immune cells of the intestinal tissue. The macromolecule-containing nanoparticles utilize epithelial M cells to enter Peyer’s patches - small areas of the intestine concentrated with particle-scavenging immune cells. In wild type mice, intestinal immune cells containing these naturally-formed nanoparticles expressed the immune tolerance-associated molecule ‘programmed death-ligand 1 (PD-L1)’, whereas in NOD1/2 double knock-out mice, which cannot recognize peptidoglycan, PD-L1 was undetected. Our results explain a role for constitutively formed calcium phosphate nanoparticles in the gut lumen and how this helps to shape intestinal immune homeostasis.

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“…PD-L1 is expressed by B and T cells, monocytes, macrophages and dendritic cells (APCs) [8] and play important role in regulating immune responses [9–12]. Moreover, over-expression of PD-L1 in a variety of tumors and in-vitro experimental models indicate compromise of immune surveillance mechanism for cancer cells in the tumor microenvironment, by interaction with PD-1 [13].…”

Section: Introductionmentioning

confidence: 99%

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

et al. 2016

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Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1− patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as a prognostic marker for PTC.

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Tissue-Expressed B7-H1 Critically Controls Intestinal Inflammation

Cited by 59 publications

References 31 publications

A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells

Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants

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