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Inflammation is a hallmark of several neurodegenerative disorders including hereditary amyloidogenic transthyretin amyloidosis (ATTRv). ATTRv is an autosomal dominant neurodegenerative disorder with extracellular deposition of mutant transthyretin (TTR) aggregates and fibrils, particularly in nerves and ganglia of the peripheral nervous system. Nerve biopsies from ATTRv patients show increased cytokine production, but interestingly no immune inflammatory cellular infiltrate is observed around TTR aggregates. Here we show that as compared to Wild Type (WT) animals, the expression of several chemokines is highly downregulated in the peripheral nervous system of a mouse model of the disease. Interestingly, we found that stimulation of mouse Schwann cells (SCs) with WT TTR results in the secretion of several chemokines, a process that is mediated by toll-like receptor 4 (TLR4). In contrast, the secretion of all tested chemokines is compromised upon stimulation of SCs with mutant TTR (V30M), suggesting that V30M TTR fails to activate TLR4 signaling. Altogether, our data shed light into a previously unappreciated mechanism linking TTR activation of SCs and possibly underlying the lack of inflammatory response observed in the peripheral nervous system of ATTRv patients. [ABSTRACT FROM AUTHOR]

4T1 metastatic breast cancer model have been widely used to study stage IV human breast cancer. However, the frequent inoculation of a large number of cells, gives rise to fast growing tumors, as well as to a surprisingly low metastatic take rate. The present work aimed at establishing the conditions enabling high metastatic take rate of the triple-negative murine 4T1 syngeneic breast cancer model. An 87% 4T1 tumor incidence was observed when as few as 500 cancer cells were implanted. 4T1 cancer cells colonized primarily the lungs with 100% efficiency, and distant lesions were also commonly identified in the mesentery and pancreas. The drastic reduction of the number of inoculated cells resulted in increased tumor doubling times and decreased specific growth rates, following a Gompertzian tumor expansion. The established conditions for the 4T1 mouse model were further validated in a therapeutic study with peguilated liposomal doxorubicin, in clinical used in the setting of metastatic breast cancer. Inoculated cell density was proven to be a key methodological aspect towards the reproducible development of macrometastases in the 4T1 mouse model and a more reliable pre-clinical assessment of antimetastatic therapies. [ABSTRACT FROM AUTHOR]

Strongyloidiasis is a neglected chronic nematode infection, in which the control of autoinfection rate and severity of disease is dependent on type 2 immune responses. Strongyloides also causes Th2 responses in the lung of infected animals and changes in airway function, including airway hyperresponsiveness (AHR). Mechanisms of AHR during Strongyloides venezuelensis infection are not entirely known, and we investigate here the role of IL-4, eosinophils, and IL-33/ST2. AHR was evaluated in infected mice by determining changes in lung function after increasing doses of methacholine. Balb/C, but no C57Bl/6, mice developed AHR, tissue eosinophilia, and increased local IL-4 and IL-5 production. Functional changes peaked at day 4 and 7, after the larva had left the lungs. AHR was clearly dependent on IL-4 but not on eosinophils, as evaluated by experiments in IL-4 and Gata-1-deficient mice. Experiments in ST2-deficient mice showed that this pathway was not needed for induction of AHR but was necessary for the maintenance of AHR and for Th2 responses in the lung. These studies clearly show a crucial role for IL-4 in the induction of AHR following S. venezuelensis infection and for IL-33/ST2 in maintaining AHR and lung Th2 responses. [ABSTRACT FROM AUTHOR]

Multiple schistosome and soil-transmitted nematode infections are frequently reported in human populations living in tropical areas of developing countries. In addition to exposure factors, the host immune response plays an important role in helminth control and morbidity in hosts with multiple infections; however, these aspects are difficult to evaluate in human populations. In the current study, female Swiss mice were simultaneously co-infected with Strongyloides venezuelensis and Schistosoma mansoni or infected with St. venezuelensis at 2, 4, or 14 weeks after Sc. mansoni infection. The simultaneously infected mice showed a similar parasite burden for St. venezuelensis compared with mono-infected mice. In contrast, there was a significant reduction of St. venezuelensis burden (primarily during the migration of the larvae) in mice that were previously infected with Sc. mansoni at the acute or chronic phase. Independent of the stage of Sc. mansoni infection, the St. venezuelensis co-infection was capable of inducing IL-4 production in the small intestine, increasing the IgE concentration in the serum and increasing eosinophilia in the lungs and intestine. This result suggests that the nematode infection stimulates local type 2 immune responses independently of the schistosomiasis stage. Moreover, previous Sc. mansoni infection stimulated early granulocyte infiltration in the lungs and trematode-specific IgM and IgG1 production that recognized antigens from St. venezuelensis infective larvae; these immune responses would act in the early control of St. venezuelensis larvae. Our data suggest that the effect of multiple helminth infections on host susceptibility and morbidity largely depends on the species of parasite and the immune response. [ABSTRACT FROM AUTHOR]

The adipose tissue can make important contributions to immune function. Nevertheless, only a limited number of reports have investigated in lean hosts the immune response elicited in this tissue upon infection. Previous studies suggested that the intracellular protozoan Neospora caninum might affect adipose tissue physiology. Therefore, we investigated in mice challenged with this protozoan if immune cell populations within adipose tissue of different anatomical locations could be differently affected. Early in infection, parasites were detected in the adipose tissue and by 7 days of infection increased numbers of macrophages, regulatory T (Treg) cells and T-bet+ cells were observed in gonadal, mesenteric, omental and subcutaneous adipose tissue. Increased expression of interferon- γ was also detected in gonadal adipose tissue of infected mice. Two months after infection, parasite DNA was no longer detected in these tissues, but T helper type 1 (Th1) cell numbers remained above control levels in the infected mice. Moreover, the Th1/Treg cell ratio was higher than that of controls in the mesenteric and subcutaneous adipose tissue. Interestingly, chronically infected mice presented a marked increase of serum leptin, a molecule that plays a role in energy balance regulation as well as in promoting Th1-type immune responses. Altogether, we show that an apicomplexa parasitic infection influences immune cellular composition of adipose tissue throughout the body as well as adipokine production, still noticed at a chronic phase of infection when parasites were already cleared from that particular tissue. This strengthens the emerging view that infections can have long-term consequences for the physiology of adipose tissue. [ABSTRACT FROM AUTHOR]

Proposed model of eosinophil participation in Schistosoma mansoni induced granuloma formation/modulation and disease severity. The absence of eosinophils during S. mansoni infection resulted in significant lower concentration of cytokines from the Th2 profile, such as IL-13, IL-5, IL33 in liver of ∆dblGATA infected mice. There was also reduction in liver concentration of IL-17, and in the regulatory cytokines, IL-10 and TGF- β. In contrast, the liver concentration of TNF- α and INF- γ increased. The changes in liver immune response observed in ∆dblGATA infected mice was accompanied by stronger activation of M1 macrophages, lower expression of COLI and COLII genes and liver content of hydroxyproline, no evident signs of granuloma modulation at chronic schistosomiasis and increase in liver damage, which would contribute to higher mortality rate of ∆dblGATA infected mice. [Display omitted] • Ablation of eosinophils did not alter the S. mansoni load in infected mice. • Infected ΔdblGATA mice displayed reduced liver Th2 and regulatory responses. • S. mansoni infection led to increased liver Th1 response in ΔdblGATA mice. • Infected ΔdblGATA mice displayed larger granulomas and more intense tissue damage. • S. mansoni infection resulted in higher mortality rate in ΔdblGATA mice. The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-β and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni , which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity. [ABSTRACT FROM AUTHOR]