Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer’s disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-κB pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

Objective. To investigate the association of ␤ 2 -glycoprotein I (␤ 2 GPI) with lipid rafts in monocytic cells and to evaluate the proinflammatory and procoagulant effects of anti-␤ 2 GPI binding to its target antigen on the monocyte plasma membrane.Methods. Human monocytes were fractionated by sucrose density-gradient centrifugation and analyzed by Western blotting. Immunoprecipitation experiments were performed to analyze the association of ␤ 2 GPI with lipid rafts and the possible interaction of ␤ 2 GPI with annexin A2 and Toll-like receptor 4 (TLR-4). Monocytes were then stimulated with affinity-purified anti-␤ 2 GPI antibodies from patients with the antiphospholipid syndrome (APS). Interleukin-1 receptor-associated kinase (IRAK) phosphorylation and NF-B activation were evaluated by immunoprecipitation and transcription factor assay, respectively. Supernatants from monocytes were tested for tumor necrosis factor ␣ (TNF␣) and tissue factor (TF) levels by enzyme-linked immunosorbent assay.Results. We found ␤ 2 GPI and its putative receptor annexin A2 in lipid raft fractions of human monocytes. Moreover, there was an association between ␤ 2 GPI and TLR-4, suggesting that it was partially dependent on raft integrity. Triggering with anti-␤ 2 GPI antibodies induced IRAK phosphorylation and consequent NF-B activation, which led to the release of TNF␣ and TF.Conclusion. Anti-␤ 2 GPI antibodies react with their target antigen, likely in association with annexin A2 and TLR-4, in lipid rafts in the monocyte plasma membrane. Anti-␤ 2 GPI binding triggers IRAK phosphorylation and NF-B translocation, leading to a proinflammatory and procoagulant monocyte phenotype characterized by the release of TNF␣ and TF, respectively. These findings provide new insight into the pathogenesis of APS, improving our knowledge of valuable therapeutic targets.

Despite inducing a strong host cellular and humoral immune response, the helminth Echinococcus granulosus is a highly successful parasite that develops, progresses, and ultimately causes chronic disease. Although surgery remains the preferred therapeutic option, pharmacological research now envisages antihelminthic strategies. To understand the mechanisms that E. granulosus uses to escape host immunosurveillance and promote chronic infection, we investigated how two hydatid cyst components, purified antigen B (AgB) and sheep hydatid fluid (SHF), act on host dendritic cell (DC) differentiation from monocyte precursors and how they influence maturation of DC that have already differentiated. We evaluated the immunomodulatory potential of these antigens by performing immunochemical and cytofluorimetric analyses of monocyte-derived DCs from healthy human donors. During monocyte differentiation, AgB and SHF downmodulated CD1a expression and upregulated CD86 expression. Compared with immature DCs differentiated in medium alone (iDCs), AgB-and SHF-differentiated cells stimulated with lipopolysaccharide included a significantly lower percentage of CD83؉ cells (P < 10 ؊4 ) and had weaker costimulatory molecule expression. When stimulated with AgB and SHF, iDCs matured and primed lymphocytes towards the Th2 response typical of E. granulosus infection. SHF and particularly AgB reduced the production of interleukin-12p70 (IL-12p70) and tumor necrosis factor alpha in lipopolysaccharide-stimulated iDCs. Anti-IL-10 antibodies increased the levels of IL-12p70 secretion in AgB-and SHF-matured DCs. AgB and SHF induced interleukin-1 receptor-associated kinase phosphorylation and activated nuclear factor-B, suggesting that Toll-like receptors could participate in E. granulosus-stimulated DC maturation. These results suggest that E. granulosus escapes host immunosurveillance in two ways: by interfering with monocyte differentiation and by modulating DC maturation.

). AgB skewed the Th1/Th2 cytokine ratios towards a preferentially immunopathology-associated Th2 polarization, predominantly in patients with progressive disease. AgB-stimulated patients' PBMC also proliferated less than SHF-stimulated PBMC (P ‫؍‬ 9 ؋ 10 ؊3 ). In vitro Th2 cytokine production was reflected in vivo by elevated specific immunoglobulin E (IgE) and IgG4 antibodies binding to AgB. These findings confirm that AgB plays a role in the escape from early immunity by inhibiting PMN chemotaxis. They also add new information on the host-parasite relationship, suggesting that AgB exploits the activation of T helper cells by eliciting a nonprotective Th2 cell response.Cystic echinococcosis (CE) is a widely endemic helminthic disease caused by infection with metacestodes (larval stage) of the tapeworm Echinococcus granulosus. It affects humans and a wide range of livestock species (28). The disease is characterized by the growth in the host internal organs, mostly liver and lungs, of steadily growing fluid-filled, unilocular cysts surrounded by a two-layered hydatid cyst wall. The main feature of the host-parasite relationship is the coexistence of the chronic infection with detectable humoral and cellular responses against the parasite. Parasite survival in vivo depends on efficient evasion mechanisms starting to operate as the parasite develops toward a hydatid cyst. A fibrotic host capsule of variable thickness usually develops, thus forming together with the parasite-derived acellular laminated layer a formidable cystic structure. As a consequence, the actively dividing germinal layer within the cyst along with its associated brood capsule and enclosed protoscoleces are effectively sequestered from the host immune responses. In addition to this physical barrier, the hydatid cyst has probably evolved other strategies for immune evasion. Although older models suggested a more passive role for parasites in immune evasion-for example sequestration, antigenic masking by host proteins, and global immunosuppression-later studies suggest in human parasitoses the active deployment of strategies that manipulate and exploit the host response (12, 30).

Atherosclerosis is a chronic multifactorial disease of the arterial wall characterized by inflammation, oxidative stress, and immune system activation. Evidence exists on a pathogenic role of oxidized red blood cells (RBCs) accumulated in the lesion after intraplaque hemorrhage. This review reports current knowledge on the impact of oxidative stress in RBC modifications with the surface appearance of senescent signals characterized by reduced expression of CD47 and glycophorin A and higher externalization of phosphatidylserine. The review summarizes findings indicating that oxidized, senescent, or stored RBCs, due to surface antigen modification and release of prooxidant and proinflammatory molecules, exert an impaired modulatory activity on innate and adaptive immune cells and how this activity contributes to atherosclerotic disease. In particular RBCs from patients with atherosclerosis, unlike those from healthy subjects, fail to control lipopolysaccharide-induced DC maturation and T lymphocyte apoptosis. Stored RBCs, accompanied by shedding of extracellular vesicles, stimulate peripheral blood mononuclear cells to release proinflammatory cytokines, augment mitogen-driven T cell proliferation, and polarize macrophages toward the proinflammatory M1 activation pathway. Collectively, literature data suggest that the crosstalk between RBCs with immune cells represents a novel mechanism by which oxidative stress can contribute to atherosclerotic disease progression and may be exploited for therapeutic interventions.