The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

BackgroundInflammasome-activated IL-1ß plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1ß (pro-IL-1ß) are still unclear. Here, we assessed the implication of alarmins (IL-1¿, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1¿ is a master cytokine that regulates IL-1ß expression.MethodsPro- and mature IL-1ß as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury.ResultsWe found that the early release of IL-1¿ and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1ß and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1ß by alveolar macrophages was significantly induced by recombinant IL-1¿ but not by IL-33. Neutralization or deletion of IL-1¿ reduced IL-1ß production and neutrophil accumulation after silica in mice. Finally, IL-1¿ released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles.ConclusionsWe demonstrated that in response to silica exposure, IL-1¿ is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1ß production. Moreover, we demonstrated that in vitro IL-1¿ release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles

Design, synthesis, And applications of galectin modulators in human health

Over the last decade, the family of galectin proteins has been identified as key regulators of important biological processes. They bind β-D-galactopyranoside residues in glycoconjugates, and by presenting multiple binding sites, within one galectin or by forming dimers or multimers, they can cross-link glycoproteins and form galectin-glycoprotein lattices. Such lattices formed on the cell surface or in vesicles have been shown to control, for example, surface residence time and signaling by receptors. Hence, compounds modulating galectin binding to their glycoprotein ligands are of potential clinical interest. This chapter describes the design and development of disubstituted thiodigalactoside derivatives that form optimal interactions with the galectin-3 binding site resulting in double-digit nanomolar affinities. Studies are discussed in which such galectin-3-modulating compounds have been important in elucidating galectin-3 mechanisms, including galectin-3 trafficking, cancer, inflammation, fibrosis, and angiogenesis. Medically relevant models using the galectin-3 modulators in characterizing macrophage alternative activation and chronic inflammation, myofibroblast activation and fibrosis, and ocular angiogenesis are discussed in more detail. In summary, the high galectin-3 affinity and definitive effects in relevant models of the disubstituted thiodigalactosides identify them as promising as lead compounds for drug development, albeit leaving a challenge in terms of optimizing PK/ADME properties