Na-AIP-1 secreted by human hookworms suppresses collagen-induced arthritis

Langdon, Kane; Buitrago, Geraldine; Pickering, Darren; Giacomin, Paul; Loukas, Alex; Haleagrahara, Nagaraja

doi:10.1007/s10787-021-00909-5

Cited by 5 publications

(2 citation statements)

References 47 publications

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“…In a mouse model of collagen-induced arthritis (CIA), inhibition of MMP-9 significantly blocked DC trafficking and delayed CIA ( He et al, 2018 ). In another study, hookworm protein Na-AIP-1 significantly suppressed CIA when used either as a monotherapy or in combination with methotrexate (MTX) ( Langdon et al, 2022 ). However, the precise mechanisms through which specific hookworm-derived proteins inhibit the various MMPs and the specific interactions mediating their function is not clearly understood and need further investigation.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Jones,

Zhan,

Ernste

et al. 2023

Front. Parasitol.

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IntroductionHookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4+Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi, the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection. MethodsFemale BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation. ResultsTreatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c+CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups. DiscussionAll in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Jones,

Zhan,

Ernste

et al. 2023

Front. Parasitol.

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“…Since the proposition of the hygiene hypothesis in 1989 [ 14 ], numerous studies have demonstrated a negative correlation between helminth infections and the incidence of autoimmune diseases such as type 1 diabetes, multiple sclerosis, and inflammatory bowel disease [ 15 ]. As research has progressed, it has been found that single components of helminth excretory–secretory proteins or helminth-derived proteins, such as the excretory–secretory antigen-62 (ES-62) from the Acanthocheilonema viteae [ 16 ], the cystatin protease inhibitor from the Schistosoma japonicum ( Sj Cystatin) [ 17 ], and the anti-inflammatory protein-1 from Necator americanus ( Na -AIP-1) [ 18 ], can ameliorate CIA. Previous studies in our laboratory have revealed that infection with Trichinella spiralis can mitigate RA by modulating the balance of CD4 + T cell differentiation [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation

Zhang,

Jiang,

et al. 2024

IJMS

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Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.

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Parasitic helminths and protozoa: Treasure boxes of disease modifying anti-rheumatic drugs

Osada,

Shimizu,

Morita

2025

Parasitology International

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Na-AIP-1 secreted by human hookworms suppresses collagen-induced arthritis

Cited by 5 publications

References 47 publications

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation

Parasitic helminths and protozoa: Treasure boxes of disease modifying anti-rheumatic drugs

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