Schistosoma “Eggs-Iting” the Host: Granuloma Formation and Egg Excretion

Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma. Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host. In humans, adult male and female worms lie within the vasculature. Here, they propagate and eggs are laid. These eggs must then be released from the host to continue the life cycle. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces. In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine. In an impressive case of exploitation of the host immune system, this process of Schistosome “eggs-iting” the host is immune dependent. In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces. We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism

The Pivotal Role of Macrophages in Metabolic Distress

Obesity is a prevalent condition with several associated co-morbidities including the development of metabolic diseases. In obesity there is immune cell infiltration into the white adipose tissue and this is associated with the generation of inflammation and insulin resistance (IR). A large majority of the infiltrating leukocytes in obese adipose tissue are pro-inflammatory macrophages, which upon activation induce a switch in metabolism from oxidative phosphorylation, as is utilised by macrophages in lean adipose tissue, towards aerobic glycolysis. The signalling pathways evoked in the recruited macrophages induce the release of pro-inflammatory cytokines, in signalling pathways which directly interfere with insulin signalling and thus induce a state of IR. As macrophages appear to play such a pivotal role in the generation of IR and are the largest leukocyte population in the adipose tissue, they provide a promising therapeutic target. Indeed, there are several strategies currently being studied to induce a ‘switch’ in macrophages associated with obese adipose tissue, towards the phenotype of those associated with lean adipose tissue, with arguably the most promising being those strategies designed to target the metabolic pathways within the macrophages. This chapter will discuss the polarisation and activation of macrophages within lean and obese adipose tissue and how these cells can be targeted therapeutically

Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses

Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back

Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses. Furthermore, within the cellular milieu of adipose tissue nutrient availability regulates differentiation and activation of T cells and changes in cellular metabolic pathways. Upon activation, T cells shift from oxidative phosphorylation to oxidative glycolysis, while the differential signaling of the kinase mammalian target of rapamycin (mTOR) and the nuclear receptor PPARγ, amongst others, drive the subsequent T cell differentiation. While the mechanisms leading to a shift from the typical type 2-dominated milieu in lean people to a Th1-biased pro-inflammatory environment during obesity are the subject of extensive research, insights on its impact on peripheral Th2-dominated immune responses become more evident. In this review, we will summarize recent findings of how Th2 cells are metabolically regulated during obesity and malnutrition, and how these states affect local and systemic Th2-biased immune responses

The Synthetic Cannabinoid R(+)WIN55,212-2 Augments Interferon-β Expression via Peroxisome Proliferator-activated Receptor-α

We have demonstrated that R()WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN- expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor- (PPAR) in mediating the effects of R()WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN- expression and R()WIN55,212-2 enhances TLR3-induced IFN- expression in a stereoselective manner via PPAR. R()WIN55,212-2 promotes increased transactivation and expression of PPAR. Using the PPAR antagonist GW6471, we demonstrate that R()WIN55,212-2 acts via PPAR to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN- promoter. Furthermore, GW6471 ameliorated the protective effects of R()WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPAR as an important mediator in manifesting the effects of R()WIN55,212-2 on the signaling cascade regulating IFN- expression. The study adds to our molecular appreciation of potential therapeutic effects of R()WIN55,212-2 in multiple sclerosis

MicroRNA-155 Protects Group 2 Innate Lymphoid Cells From Apoptosis to Promote Type-2 Immunity.

Group-2 innate lymphoid cells (ILC2) play critical roles in the initiation and maintenance of type-2 immune responses, predominantly through their production of the type-2 cytokines IL-5, IL-9, and IL-13. ILC2 are essential for the efficient elimination of helminth parasites, but also contribute to the detrimental type-2 immune responses that underlie diseases such as asthma and allergy. While several transcription factors have been identified that regulate the development and function of ILC2, less is known about the post-transcriptional mechanisms that regulate these processes. We identified micro-RNAs (miRNAs) that are co-ordinately regulated in ILC2 from mice exposed to two different stimuli, namely IL-33 "alarmin" administration or Nippostrongylus brasiliensis parasitic worm infection. miR-155 is upregulated in ILC2 in response to both stimuli and miR-155-/- mice had impaired IL-33-driven ILC2 responses. Using mixed bone marrow chimeras, we demonstrate that this deficit is intrinsic to ILC2 and that miR-155 protects ILC2 from apoptosis, while having little impact on ILC2 proliferation or cytokine production. These data reveal a subset of miRNAs that are regulated upon ILC2 activation and establish a specific role for miR-155 in regulating ILC2 survival following activation

Role for Retinoic Acid-Related Orphan Receptor Alpha (RORα) Expressing Macrophages in Diet-Induced Obesity

The transcription factor RORα plays an important role in regulating circadian rhythm, inflammation, metabolism, and cellular development. Herein we show a role for RORα-expressing macrophages in the adipose tissue in altering the metabolic state of mice on a high-fat diet. The expression of Rora and RORA is elevated in white adipose tissue from obese mice and humans when compared to lean counterparts. When fed a high-fat diet Rora reporter mice revealed increased expression of Rora-YFP in macrophages in white adipose tissue deposits. To further define the potential role for Rora-expressing macrophages in the generation of an aberrant metabolic state Rorafl/flLysMCre/+ mice, which do not express Rora in myeloid cells, were maintained on a high-fat diet, and metabolic parameters assessed. These mice had significantly impaired weight gain and improved metabolic parameters in comparison to Rorafl/fl control mice. Further analysis of the immune cell populations within white adipose tissue deposits demonstrates a decrease in inflammatory adipose tissue macrophages (ATM). In obese reporter mouse there was increased in Rora-YFP expressing ATM in adipose tissue. Analysis of peritoneal macrophage populations demonstrates that within the peritoneal cavity Rora-expression is limited to myeloid-derived macrophages, suggesting a novel role for RORα in macrophage development and activation, which can impact on metabolism, and inflammation