The role of hybrid ubiquitin chains in the MyD88 and other innate immune signalling pathways

The adaptor protein MyD88 is required for signal transmission by Toll-like Receptors (TLRs) and receptors of the interleukin 1 (IL-1) family of cytokines. MyD88 signalling triggers the formation of Lys63-linked and Met1-linked ubiquitin (K63-Ub, M1-Ub) chains within minutes. The K63-Ub chains, which are formed by the E3 ubiquitin ligases TRAF6, Pellino1 and Pellino2, activate TAK1, the master kinase that switches on mitogen-activated protein (MAP) kinase cascades and initiates activation of the canonical IκB kinase (IKK) complex. The M1-Ub chains, which are formed by the Linear Ubiquitin chain Assembly Complex (LUBAC), bind to the NEMO component of the IKK complex and are required for TAK1 to activate IKKs, but not MAP kinases. An essential E3 ligase-independent role of TRAF6 is to recruit LUBAC into the MyD88 signalling complex, where it recognises preformed K63-Ub chains attached to protein components of these complexes, such as IRAK1, producing ubiquitin chains containing both types of linkage, termed K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids, which is a feature of several innate immune signalling pathways, permits the co-recruitment of proteins that interact with either K63-Ub or M1-Ub chains. Two likely roles for K63/M1- Ub hybrids are to facilitate the TAK1-dependent activation of the IKK complex and to prevent the hyper-activation of these kinases by recruiting A20 and A20-binding inhibitor of NF-κB1 (ABIN1). These proteins restrict activation of the TAK1 and IKK complexes, probably by competing with them for binding to K63/M1-Ub hybrids. The formation of K63/M1-Ub hybrids may also regulate the rate at which the ubiquitin linkages in these chains are hydrolysed. The IKK-catalysed phosphorylation of some of its substrates permits their recognition by the E3 ligase SCFβ TRCP, leading to their Lys48-linked ubiquitylation and proteasomal degradation. Innate immune signalling is therefore controlled by the formation and destruction of three different types of ubiquitin linkage

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis

AMP Affects Intracellular Ca2+ Signaling, Migration, Cytokine Secretion and T Cell Priming Capacity of Dendritic Cells

The nucleotide adenosine-5′-monophosphate (AMP) can be released by various cell types and has been shown to elicit different cellular responses. In the extracellular space AMP is dephosphorylated to the nucleoside adenosine which can then bind to adenosine receptors. However, it has been shown that AMP can also activate A1 and A2a receptors directly. Here we show that AMP is a potent modulator of mouse and human dendritic cell (DC) function. AMP increased intracellular Ca2+ concentration in a time and dose dependent manner. Furthermore, AMP stimulated actin-polymerization in human DCs and induced migration of immature human and bone marrow derived mouse DCs, both via direct activation of A1 receptors. AMP strongly inhibited secretion of TNF-α and IL-12p70, while it enhanced production of IL-10 both via activation of A2a receptors. Consequently, DCs matured in the presence of AMP and co-cultivated with naive CD4+CD45RA+ T cells inhibited IFN-γ production whereas secretion of IL-5 and IL-13 was up-regulated. An enhancement of Th2-driven immune response could also be observed when OVA-pulsed murine DCs were pretreated with AMP prior to co-culture with OVA-transgenic naïve OTII T cells. An effect due to the enzymatic degradation of AMP to adenosine could be ruled out, as AMP still elicited migration and changes in cytokine secretion in bone-marrow derived DCs generated from CD73-deficient animals and in human DCs pretreated with the ecto-nucleotidase inhibitor 5′-(alpha,beta-methylene) diphosphate (APCP). Finally, the influence of contaminating adenosine could be excluded, as AMP admixed with adenosine desaminase (ADA) was still able to influence DC function. In summary our data show that AMP when present during maturation is a potent regulator of dendritic cell function and point out the role for AMP in the pathogenesis of inflammatory disorders

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Degradation of Alumina and Magnesia Chrome refractory bricks in Portland cement kiln – Corrected version*

In cement plants, the refractory products are particularly confronted to partially liquid oxide phases at temperature ranging between 900°C and 1700°C. All constituents of these products have to resist not only to thermal constraints, but also to the thermochemical solicitations which result from contact material/coating. In order to study the phenomenon of degradation of refractory bricks in cement kilns and to identify the causes of their degradation, we proceed to the examination of industrial cases in cement kiln. Many chemical tests of the degraded refractory bricks have been done and the results acquired were compared to the ones not used. The analysis of the results is doing using different techniques (Loss of ignition, X-ray Fluorescence, X-ray Diffraction). The results show that the degradation of the used bricks in the clinkering and cooling zone is due to the infiltration of aggressive elements such us sulphur, alkali (Na2O, K2O ...). The chemical interaction between the Portland clinker phases and refractory material has also an importance on the stability of the coating and consequently on the life of the refractories

Withdrawn article – Degradation of Alumina and Magnesia Chrome refractory bricks in Portland cement kiln

This paper published in MATEC Web of Conferences has been formally withdrawn. It should not be cited or referred to in the future. A corrected version replaces this article, see MATEC Web of Conferences 11 01048 (2014), DOI: 10.1051/matecconf/20141101048. Request approved by the Editors and the Publisher on May 15, 2014

Withdrawn article – Degradation of Alumina and Magnesia Chrome refractory bricks in Portland cement kiln

This paper published in MATEC Web of Conferences has been formally withdrawn. It should not be cited or referred to in the future. A corrected version replaces this article, see MATEC Web of Conferences 11 01048 (2014), DOI: 10.1051/matecconf/2014110104

Mineralogical stabilization of Ternesite in Belite Sulfo-Aluminate Clinker elaborated from limestone, shale and phosphogypsum

This paper investigates the mineralogical evolution of sulfoaluminate clinker elaborated from moroccan prime materials limestone, shale and phosphogypsum as a byproduct from phosphoric acid factories. The advantage of the production of this type of clinker is related to the low clinkerisation temperature which is known around 1250°C, and to less consumption quantity of limestone thus enabling less CO2 emissions during the decarbonation process compared to that of Portland cement. In this study we determine the stability conditions of belite sulfoaluminate clinker containing belite (C2S) ye’elimite (C4A3$) and ternesite (C5S2$). The hydration compounds of this clinker are also investigated. The monitoring of the synthesized and hydrated phases is performed by X-Ray Diffraction and Infrared spectroscopy. The results show the formation of ternesite at 800°C and the stabilization of clinker containing y’elminite, belite and ternesite at temperatures between 1100 and 1250°C

Mineralogical stabilization of Ternesite in Belite Sulfo-Aluminate Clinker elaborated from limestone, shale and phosphogypsum

This paper investigates the mineralogical evolution of sulfoaluminate clinker elaborated from moroccan prime materials limestone, shale and phosphogypsum as a byproduct from phosphoric acid factories. The advantage of the production of this type of clinker is related to the low clinkerisation temperature which is known around 1250°C, and to less consumption quantity of limestone thus enabling less CO2 emissions during the decarbonation process compared to that of Portland cement. In this study we determine the stability conditions of belite sulfoaluminate clinker containing belite (C2S) ye’elimite (C4A3$) and ternesite (C5S2$). The hydration compounds of this clinker are also investigated. The monitoring of the synthesized and hydrated phases is performed by X-Ray Diffraction and Infrared spectroscopy. The results show the formation of ternesite at 800°C and the stabilization of clinker containing y’elminite, belite and ternesite at temperatures between 1100 and 1250°C