Eicosanoids tailor the innate immune response by supporting local inflammation and exhibiting immunomodulatory properties. Prostaglandin (PG) E 2 is the most abundant eicosanoid in the inflammatory milieu due to the robust production elicited by pathogen-associated molecular patterns on cells of the innate immune system. The different functions and cell distribution of E prostanoid receptors explain the difficulty encountered thus far to delineate the actual role of PGE 2 in the immune response. The biosynthesis of eicosanoids includes as the first step the Ca 21 -and kinase-dependent activation of the cytosolic phospholipase A 2 , which releases arachidonic acid from membrane phospholipids, and later events depending on the transcriptional regulation of the enzymes of the cyclooxygenase routes, where PGE 2 is the most relevant product. Acting in an autocrine/ paracrine manner in macrophages, PGE 2 induces a regulatory phenotype including the expression of interleukin (IL)-10, sphingosine kinase 1, and the tumor necrosis factor family molecule LIGHT. PGE 2 also stabilizes the suppressive function of myeloidderived suppressor cells, inhibits the release of IL-12 p70 by macrophages and dendritic cells, and may enhance the production of IL-23. PGE 2 is a central component of the inflammasomedependent induction of the eicosanoid storm that leads to massive loss of intravascular fluid, increases the mortality rate associated with coinfection by Candida ssp. and bacteria, and inhibits fungal phagocytosis. These effects have important consequences for the outcome of infections and the polarization of the immune response into the T helper cell types 2 and 17 and can be a clue to develop pharmacological tools to address infectious, autoimmune, and autoinflammatory diseases.

Backgroundβ-glucans are fungal cell wall components that bind to the C-type lectin-like receptor dectin-1. Polymorphisms of dectin-1 gene are associated with susceptibility to invasive fungal infection and medically refractory ulcerative colitis. The purpose of this study has been addressing the response of human macrophages to β-glucans under different conditions mimicking the composition of the inflammatory milieu in view of the wide plasticity and large range of phenotypical changes showed by these cells, and the relevant role of dectin-1 in several pathophysiological conditions.Principal FindingsSerum-differentiated macrophages stimulated with β-glucans showed a low production of TNFα and IL-1β, a high production of IL-6 and IL-23, and a delayed induction of cyclooxygenase-2 and PGE2 biosynthesis that resembled the responses elicited by crystals and those produced when phagosomal degradation of the phagocytic cargo increases ligand access to intracellular pattern recognition receptors. Priming with a low concentration of LPS produced a rapid induction of cyclooxygenase-2 and a synergistic release of PGE2. When the differentiation of the macrophages was carried out in the presence of M-CSF, an increased expression of dectin-1 B isoform was observed. In addition, this treatment made the cells capable to release arachidonic acid in response to β-glucan.ConclusionsThese results indicate that the macrophage response to fungal β-glucans is strongly influenced by cytokines and microbial-derived factors that are usual components of the inflammatory milieu. These responses can be sorted into three main patterns i) an elementary response dependent on phagosomal processing of pathogen-associated molecular patterns and/or receptor-independent, direct membrane binding linked to the immunoreceptor tyrosine-based activation motif-bearing transmembrane adaptor DNAX-activating protein 12, ii) a response primed by TLR4-dependent signals, and iii) a response dependent on M-CSF and dectin-1 B isoform expression that mainly signals through the dectin-1 B/spleen tyrosine kinase/cytosolic phospholipase A2 route.

Background: Phagocytosis and Th17 immune response control fungal invasion. Results: ␤-Glucans mobilize nuclear C/EBP homologous protein (CHOP) and increase activating transcription factor 2 (ATF2) binding to the il23a promoter. Conclusion: ␤-Glucans direct proapoptotic CHOP to phagosomal vesicles and induce ATF2-dependent il23a transcription. Significance: The mechanisms underlying the unfolded protein response and the trans-activation of il23a elicited by ␤-glucans are ascertained.

Merino J. Enhanced sensitivity of flow cytometry for routine assessment of minimal residual disease. Haematologica. 2010; 95:691-692. doi:10.3324/haematol.2009 (approximately 20-30, 40-60, and 80-200 © F e r r a t a S t o r t i F o u n d a t i o n Minimal residual disease (MRD) was measured in samples from 5 patients with multiple myeloma (MM), 5 patients with B-cell chronic lymphocytic leukemia (B-CLL), and 4 patients with T-cell lymphoproliferative disorders (T-CLPD) by detecting three different levels of malignant cells