Trichinella spiralis Excretory–Secretory Products Induce Tolerogenic Properties in Human Dendritic Cells via Toll-Like Receptors 2 and 4

Abstract

Trichinella spiralis, as well as its muscle larvae excretory–secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-β, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF-β- producing CD4+CD25hiFoxp3hi T cells in indolamine 2, 3 dioxygenase (IDO)-1-dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders.

Excretory/Secretory Products From Trichinella spiralis Adult Worms Attenuated DSS-Induced Colitis in Mice by Driving PD-1-Mediated M2 Macrophage Polarization

“…It is necessary to identify the specific molecules in the ES products involved in immunomodulation (46). LC-MS/MS identified more than 280 protein components in T. spiralis AES with 4 proteins having potential regulatory functions that include cysteine protease inhibitor, serine protease, 53 kDa excretory/secretory antigen, and glutathione-S-transferase (47)(48)(49). Some of the proteins secreted by the T. spiralis adult worm have revealed regulatory functions to the host immune system.…”

Trichinella spiralis:inflammation modulator

“…Thirteen mammalian TLR paralogues have now been identified (ten in humans and 12 in mice) (Beiting et al, 2004). TLR1-TLR9 were more studied in the murine disease model correlated with human beings (Yu et al, 2013;Kim et al, 2015;Sun et al, 2015;Ilic et al, 2018;Wojtkowiak-Giera et al, 2018). Different stages of T. spiralis infection had different impacts on the expression of TLR1-TLR9 (Yu et al, 2013;Kim et al, 2015).The expression of TLR4 and TLR9 significantly increases in the small intestine after T. spiralis infects the intestine and releases ES molecules compared with TLR1, TLR2 and TLR5 Table 1.…”

“…2). Therefore, TLR4 may be more closely associated with the Th2 response in individuals who are infected with T. spiralis compared with those of other TLRs (Ilic et al, 2018;Wojtkowiak-Giera et al, 2018). DCs could produce interleukin (IL)-12, which influences the development of Th1 or IL-4 and influences the development of Th2 type of immune response in response to pathogen associated molecular patterns (PAMPS) and damage-associated molecular pattern molecules (Qian & Cao, 2018).…”

“…The regulation of DCs occurs in a generalized manner irrespective of their Th1 or Th2 phenotypic affiliation (Mucida & Cheroutre, 2010). Gruden-Movsesijan et al (2010) successfully induced an immune tolerogenic, Th2 response using T. spiralis-sensitized DCs in rats and humans (Ilic et al, 2018). This is a promising tool to avoid the application of live parasites to treat various autoimmune and allergic diseases.…”

Trichinella spiralis Thioredoxin Peroxidase 2 Regulates Protective Th2 Immune Response in Mice by Directly Inducing Alternatively Activated Macrophages

“…During the enteric phase, T. spiralis infection induces a Th1/Th2 mixed response, while in the systemic phase, the response is Th2-biased (28). During the transformation of immune responses, excretory-secretory (ES) products from the T. spiralis have been reported to play a crucial role in inhibiting inflammation (29) which can protect the parasite and the host at the same time (18,19,30). So far, only a structural molecule, chitin, has been identified to modulate the macrophage to the alternative phenotype (4,31).…”