Abstract
Helminth parasites modulate immune responses in their host to prevent their elimination and to establish chronic infections. Our previous studies indicate that Taenia crassiceps-excreted/secreted antigens (TcES) downregulate inflammatory responses in rodent models of autoimmune diseases, by promoting the generation of alternatively activated-like macrophages (M2) in vivo. However, the molecular mechanisms triggered by TcES that modulate macrophage polarization and inflammatory response remain unclear. Here, we found that, while TcES reduced the production of inflammatory cytokines (IL-6, IL-12, and TNFα), they increased the release of IL-10 in LPS-induced bone marrow-derived macrophages (BMDM). However, TcES alone or in combination with LPS or IL-4 failed to increase the production of the canonical M1 or M2 markers in BMDM. To further define the anti-inflammatory effect of TcES in the response of LPS-stimulated macrophages, we performed transcriptomic array analyses of mRNA and microRNA to evaluate their levels. Although the addition of TcES to LPS-stimulated BMDM induced modest changes in the inflammatory mRNA profile, it induced the production of mRNAs associated with the activation of different receptors, phagocytosis, and M2-like phenotype. Moreover, we found that TcES induced upregulation of specific microRNAs, including miR-125a-5p, miR-762, and miR-484, which are predicted to target canonical inflammatory molecules and pathways in LPS-induced BMDM. These results suggest that TcES can modulate proinflammatory responses in macrophages by inducing regulatory posttranscriptional mechanisms and hence reduce detrimental outcomes in hosts running with inflammatory diseases.
Highlights
Helminth infections induce polarized TH2-type biased immune responses that play a role in parasite expulsion, tissue repair, and regulation of unrelated inflammatory and autoimmune responses in the host [1,2,3]
The effect of TcES in counteracting detrimental inflammatory responses in vivo is associated with the emergence of polarized macrophages towards an Alternatively activated-like macrophages (M2) phenotype [4, 5, 11]
We have previously demonstrated that infection with the helminth parasite T. crassiceps or the administration of TcES reduced the symptoms of EAE, type I diabetes, and ulcerative colitis, in part due to the polarization of macrophages in vivo towards an M2 phenotype [4,5,6,7,8, 26]
Summary
Helminth infections induce polarized TH2-type biased immune responses that play a role in parasite expulsion, tissue repair, and regulation of unrelated inflammatory and autoimmune responses in the host [1,2,3]. The ability of T. crassiceps and TcES to counteract these inflammatory responses was demonstrated to be dependent on a population of macrophages that produced markers of alternative activation (M2), such as PD-L2, IL-4Rα, MR, IL-10, ARG1, YM1, and FIZZ1 [9]. Released IFN-γ and pathogen or danger-associated molecular patterns (PAMPs or DAMPs) during infections or tissue injury, respectively, promote classical (M1) activation in macrophages [1, 12]. A crucial role for T. crassiceps-induced M2 macrophages in regulating detrimental autoimmune and inflammatory responses has been demonstrated [3], the transcriptional events elicited by TcES that modulate macrophage activation have not been elucidated
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