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Treatments for Inflammation

Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver

Authors

Saurav Roy Choudhury, Liane Babes, Jennifer J. Rahn, Bo-Young Ahn, Kimberly-Ann R. Goring, Jennifer C. King, Arthur Lau, Björn Petri, Xiaoguang Hao, Andrew K. Chojnacki, Ajitha Thanabalasuriar, Erin F. McAvoy, Sébastien Tabariès, Christoph Schraeder, Kamala D. Patel, Peter M. Siegel, Karen A. Kopciuk, David C. Schriemer, Daniel A. Muruve, Margaret M. Kelly, Bryan G. Yipp, Paul Kubes, Stephen M. Robbins, Donna L. Senger

Overview

Cell VOLUME 178, ISSUE 5, P1205-1221.E17, AUGUST 22, 2019. DOI:https://doi.org/10.1016/j.cell.2019.07.017 

Highlights

- Dipeptidase 1 (DPEP1) serves as a vascular adhesion molecule in lungs and liver
- DPEP1 acts as a physical adhesion receptor independent of its dipeptidase activity
- Targeting DPEP1 reduces mortality in murine models of sepsis

 

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Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury

Authors

Lau A, Chung H, Komada T, Platnich JM, Sandall CF, Choudhury SR, Chun J, Naumenko V, Surewaard BG, Nelson MC, Ulke-Lemée A, Beck PL, Benediktsson H, Jevnikar AM, Snelgrove SL, Hickey MJ, Senger DL, James MT, Macdonald JA, Kubes P, Jenne CN, Muruve DA

Overview

J Clin Invest. 2018 Jul 2;128(7):2894-2913. doi: 10.1172/JCI96640. Epub 2018 Jun 4.

 

Abstract

Radiographic contrast agents cause acute kidney injury (AKI), yet the underlying pathogenesis is poorly understood. Nod-like receptor pyrin containing 3–deficient (Nlrp3-deficient) mice displayed reduced epithelial cell injury and inflammation in the kidney in a model of contrast-induced AKI (CI-AKI). Unexpectedly, contrast agents directly induced tubular epithelial cell death in vitro that was not dependent on Nlrp3. Rather, contrast agents activated the canonical Nlrp3 inflammasome in macrophages. Intravital microscopy revealed diatrizoate (DTA) uptake within minutes in perivascular CX3CR1+ resident phagocytes in the kidney. Following rapid filtration into the tubular luminal space, DTA was reabsorbed and concentrated in tubular epithelial cells via the brush border enzyme dipeptidase-1 in volume-depleted but not euvolemic mice. LysM-GFP+ macrophages recruited to the kidney interstitial space ingested contrast material transported from the urine via direct interactions with tubules. CI-AKI was dependent on resident renal phagocytes, IL-1, leukocyte recruitment, and dipeptidase-1. Levels of the inflammasome-related urinary biomarkers IL-18 and caspase-1 were increased immediately following contrast administration in patients undergoing coronary angiography, consistent with the acute renal effects observed in mice. Taken together, these data show that CI-AKI is a multistep process that involves immune surveillance by resident and infiltrating renal phagocytes, Nlrp3-dependent inflammation, and the tubular reabsorption of contrast via dipeptidase-1.

NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis

Authors

Hirota SA, Ng J, Lueng A, Khajah M, Parhar K, Li Y, Lam V, Potentier MS, Ng K, Bawa M, McCafferty DM, Rioux KP, Ghosh S, Xavier RJ, Colgan SP, Tschopp J, Muruve D, Macdonald JA, Beck PL.

Overview

Inflamm Bowel Dis. 2011 Jun;17(6):1359-72. doi: 10.1002/ibd.21478. Epub 2010 Sep 24. PubMed PMID: 20872834; PubMed Central PMCID:PMC3026862

BACKGROUND: Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn's disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18.

METHODS: In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3(-/-) and wildtype mice were assessed in the dextran sulfate sodium and 2,4,6-trinitrobenzenesulfonic acid models of experimental colitis.

RESULTS: Nlrp3(-/-) mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β, reduced antiinflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3(-/-) mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3(-/-) mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions, and a unique intestinal microbiota.

CONCLUSIONS: Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.

The NLRP3 inflammasome promotes renal inflammation and contributes to CKD

Authors

Vilaysane A, Chun J, Seamone ME, Wang W, Chin R, Hirota S, Li Y, Clark SA, Tschopp J, Trpkov K, Hemmelgarn BR, Beck PL, Muruve DA.

Overview

J Am Soc Nephrol. 2010 Oct;21(10):1732-44. Epub 2010 Aug 5. PubMed PMID: 20688930; PubMed Central PMCID:PMC3013544

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3(-/-) mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.

More Articles ...

  • Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome

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March 4th 2021

ARCH Scientist Publishes Paper Showing Pre-Clinical Efficacy of AB569 in Eradicating Multi-Drug Resistant Pathogens Acinetobacter baumannii and Acinetobacter spp

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February 26th 2021

Peter Lougheed Centre Joins the Phase II Trial of LSALT Peptide for the Treatment of Complications in Hospitalized COVID-19 Patients

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Treatments for Inflammation
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