The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells

Loser, Karin; Vogl, Thomas; Voskort, Maik; Lueken, Aloys; Kupas, Verena; Nacken, Wolfgang; Klenner, Lars; Kuhn, Annegret; Foell, Dirk; Sorokin, Lydia; Luger, Thomas A.; Roth, Johannes; Beissert, Stefan

doi:10.1038/nm.2150

Cited by 277 publications

(262 citation statements)

References 28 publications

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“…It is possible that eukaryotes evolved a defense mechanism that takes advantage of the preferential incorporation of Mn by pathogens in critical enzymes. In addition to having direct antimicrobial properties, CP is a known activator of the cell-surface receptors toll-like receptor 4 and receptor for advanced glycation end products and acts as a chemoattractant for macrophages (38,39). Based on the observation that Mn results in structural ordering of the S100A9 C-terminal tail, it is intriguing to speculate that Mn-bound CP may have different immunomodulatory properties than Zn-bound or metal-free CP.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Damo

Kehl-Fie

Sugitani

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

340

594

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The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn 2+ and Zn 2+ with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn 2+ sequestration. The asymmetry of the CP heterodimer creates a single Mn 2+ -binding site from six histidine residues, which distinguishes CP from all other Mn 2+ -binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn 2+ and Zn 2+ being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn 2+ sequestration. These data establish the importance of Mn 2+ sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.bacterial pathogenesis | Staphylococcus aureus | antibiotic resistance | protein crystal structure | isothermal titration calorimetry B acterial pathogens are a significant threat to global public health. This threat is compounded by the fact that these organisms are rapidly becoming resistant to all relevant antimicrobials. Of particular note is the recent emergence of antibiotic-resistant strains of Staphylococcus aureus as a leading cause of bacterial infection in the United States (1) and arguably the most important threat to the public health of the developed world. Consequently, the identification of therapeutics to treat bacterial pathogens is paramount to our continued ability to limit this infectious threat.One promising area of potential therapeutic development involves targeting bacterial access to essential transition metals. This strategy is based on the fact that all bacterial pathogens require these nutrient metals to colonize their hosts (2-5). In vertebrates, the bacterial need for nutrient transition metals is counteracted by the sequestration of these metals by the host. This limitation of essential nutrients, termed "nutritional immunity," is a potent defense against infection (6). Although a variety of metals is required for microbial growth, studies of nutritional immunity have been primarily restricted to the struggle for iron (Fe) between host and pathogen (7-9).An innate immune factor, calprotectin (CP), is abundant in neutrophils and plays a key role in nutritional immunity. CP can be found at sites of infection in excess of 1 mg/mL and is required for the control of a number of medically relevant bacteria and fungi including S. aureus, Candida albicans, and Aspergillus fumigates (10-14). The antimicrobial activity of CP is due to the chelation of the essential nutrients Zn 2+ (Zn) and Mn 2+ (Mn), which results in bacterial metal starvation and is reversed by the addition of these metals in excess (11, 13). Moreover, CP-deficient mice have increased microbial burdens following systemic challenge, und...

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Section: Discussionmentioning

confidence: 99%

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Damo

Kehl-Fie

Sugitani

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

340

594

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“…S100A8 forms a heterodimer with S100A9, and the complex is one of the most powerful endogenous ligands for TLR4, which is essential for full activation of macrophages endotoxin-induced shock and vascular and autoimmune disorders [24,31,32]. TLR4 signalling also plays an important role in the development of various kidney diseases, yet the role of TLR4 in diabetic glomerulopathy or hyperlipidaemiainduced kidney damage remains to be elucidated [8][9][10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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“…Exp. (2014) 62:449-458 453 the induction of pathogenic Tc17 cells and to the development of systemic autoimmunity in mice and humans (Loser et al 2010). Taken together, there is strong evidence for a pathogenic function of Tc17 cells in autoimmune diseases.…”

Section: Cd8 ? T Cells Lacking Both T-bet and Eomes Fail To Differementioning

confidence: 99%

“…T cells, a subpopulation of adaptive lymphocytes, play an important role in immunity to intracellular pathogens and tumors (Gattinoni et al 2012;Klenerman and Hill 2005;Kuang et al 2010;Lu et al 2014). They also contribute to the regulation of pathologic processes such as autoimmune and allergic disorders (Huber et al 2009;Kim and Cantor 2011;Loser et al 2010;Tang et al 2012;Visekruna et al 2013). Naïve CD8…”

Section: Cd8mentioning

confidence: 99%

Heterogeneity in the Differentiation and Function of CD8+ T Cells

Mittrücker

Visekruna

Huber

2014

Arch. Immunol. Ther. Exp.

241

215

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It is well established that CD8? T cells constitute an important branch of adaptive immunity contributing to clearance of intracellular pathogens and providing long-term protection. These functions are mostly fulfilled by the best characterized subpopulation of CD8? T cells, the cytotoxic T lymphocytes (also called Tc1 cells), owing to their ability to kill infected cells and to secrete cytokines such as interferon-c and tumor necrosis factor-a. However, there is growing evidence for alternative CD8?

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The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells

Cited by 277 publications

References 28 publications

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Heterogeneity in the Differentiation and Function of CD8+ T Cells

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