A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease

Alvarado, Raquel; O’Brien, Bronwyn A.; Tanaka, Akane; Dalton, John P.; Donnelly, Sheila

doi:10.1016/j.imbio.2014.11.008

Cited by 19 publications

(15 citation statements)

References 90 publications

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“…In addition to PGE2, other worm products act as immune modulators, indicating that helminths have evolved different mechanisms to modulate host immunity. Examples of such helminth products are defense molecules in Fasciola hepatica (46), the phosphorylcholine moiety of ES‐62 in Acanthocheilonema viteae (47, 48), and Omega‐1 in…”

Section: Methodsmentioning

confidence: 99%

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells

et al. 2016

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Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S. M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.

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Section: Methodsmentioning

confidence: 99%

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells

et al. 2016

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“…Helminth defense molecules (HDMs) are a newly discovered family of secreted immunomodulatory proteins that share biochemical and structural characteristics with the mammalian “cathelicidin-like” host defense peptides (HDP) (149). HDPs are found in both the animal and plant kingdoms and play important roles in innate immune defense against parasites, fungi, bacteria, and viruses (150).…”

Section: Immune Modulating Excretory Secretory Productsmentioning

confidence: 99%

Helminth Immunomodulation in Autoimmune Disease

et al. 2017

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Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating “talents” of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

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“…Among the enzyme secreted in this way, we found the acid phosphatase which gives a yellow color when reacting with PNPP (Alvarado et al 2015). The tested molecules revealed inhibiting effects against the cellular lysosomal enzyme activity, suggesting that the unaffected and treated naringenins prevent the development of autoimmune responses (Alvarado et al 2015). These results aside, macrophage phagocytosis is attended by the release of free radicals and other reactive nitrogen species (RNS, the latter comprising nitric oxide) involved in pathogen destroying (Manosroi et al 2005).…”

Section: Discussionmentioning

confidence: 93%

“…This process renders the internalized molecules disposed to degradation by the lysosomal hydrolases (Bright et al 2005;Luzio et al 2007). Among the enzyme secreted in this way, we found the acid phosphatase which gives a yellow color when reacting with PNPP (Alvarado et al 2015). The tested molecules revealed inhibiting effects against the cellular lysosomal enzyme activity, suggesting that the unaffected and treated naringenins prevent the development of autoimmune responses (Alvarado et al 2015).…”

Section: Discussionmentioning

confidence: 93%

Effect of heated naringenin on immunomodulatory properties and cellular antioxidant activity

Maâtouk

Elgueder

Mustapha

et al. 2016

Cell Stress and Chaperones

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Naringenin is one of the most popular flavonoids derived from citrus. It has been reported to be an effective antiinflammatory compound. Citrus fruit may be used raw, cooked, stewed, or boiled. The present study was conducted to investigate the effect of thermal processes on naringenin in its immunomodulatory and cellular antioxidant activities. The effects of flavonoids on B and T cell proliferation were assessed on splenocytes stimulated or not with mitogens. However, their effects on cytotoxic T lymphocyte (CTL) and natural killer (NK) activities were assessed in splenocytes co-incubated with target cells. The amount of nitric oxide production and the lysosomal enzyme activity were evaluated in vitro on mouse peritoneal macrophages. Cellular antioxidant activity in splenocytes and macrophages was determined by measuring the fluorescence of the dichlorofluorescin (DCF). Our findings revealed that naringenin induces B cell proliferation and enhances NK activity. The highest concentration of native naringenin exhibits a significant proliferation of T cells, induces CTL activity, and inhibits cellular oxidation in macrophages. Conversely, it was observed that when heatprocessed, naringenin improves the cellular antioxidant activity in splenocytes, increases the cytotoxic activity of NK cells, and suppresses the cytotoxicity of T cells. However, heat treatment maintains the anti-inflammatory potency of naringenin.

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A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease

Cited by 19 publications

References 90 publications

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells

Helminth Immunomodulation in Autoimmune Disease

Effect of heated naringenin on immunomodulatory properties and cellular antioxidant activity

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