The Anti-Inflammatory Immune Response in Early Trichinella spiralis Intestinal Infection Depends on Serine Protease Inhibitor–Mediated Alternative Activation of Macrophages

Abstract

Trichinella spiralis is recognized for its ability to regulate host immune responses via excretory/secretory (ES) products. Serine protease inhibitors (serpins) play an important role in ES product-mediated immunoregulatory effects during T. spiralis infection. In this study, the immunoregulatory properties of a serpin derived from T. spiralis (Ts-serpin) were explored in BALB/c mice. The results showed that naturally occurring Ts-serpin was detected in the stichosomes of muscle larvae and adult worms. Moreover, enhancing (by injection of a soluble-expressed recombinant Ts-serpin [rTs-serpin]) or blocking (by passive immunization with anti-rTs-serpin serum) the effects of Ts-serpin changed the levels of cytokines related to inflammation induced by T. spiralis infection in the serum, mesenteric lymph nodes, and peritoneal cavity, which then led to a change in the adult worm burden in early T. spiralis infection. Moreover, the phenotypic changes in peritoneal macrophages were found to be related to Ts-serpinmediated immunoregulation. Furthermore, a STAT6 activation mechanism independent of IL-4Ra has been found to regulate protein-mediated alternative activation of bone marrow-derived macrophages and mimic the immunoregulatory role of Ts-serpin in T. spiralis infection. Finally, the anti-inflammatory properties of rTs-serpin and bone marrow-derived macrophage alternative activation by rTs-serpin were demonstrated using a trinitrobenzene sulfonic acid-induced inflammatory bowel disease model. In summary, a protein-triggered anti-inflammatory mechanism was found to favor the survival of T. spiralis in the early stage of infection and help to elucidate the immunoregulatory effects of T. spiralis on the host immune response.

Extracellular vesicles from Trichinella spiralis: Proteomic analysis and protective immunity

“…It has been reported that T . spiralis SPI could induce the alternative activation of BMDMs, which contributed to the parasitism of parasites [ 35 ]. Moreover, it has been proved that Ts -ML-EVs could inhibit M1 macrophage polarization to prevent colitis [ 19 ].…”

“…"Molecular function" analysis revealed that Ts-ML-EVs proteins were significantly enriched in serine-type endopeptidase, including serine protease inhibitor Kazal-type 4, which belongs to a conserved superfamily, serine protease inhibitor (SPI) family. It has been reported that T. spiralis SPI could induce the alternative activation of BMDMs, which contributed to the parasitism of parasites [35]. Moreover, it has been proved that Ts-ML-EVs could inhibit M1 macrophage polarization to prevent colitis [19].…”

Nrf2 Participates in M2 Polarization by Trichinella spiralis to Alleviate TNBS-Induced Colitis in Mice

“…Bone marrow-derived macrophages (BMDM) were generated from murine bone marrow cells as described previously ( 19 ). Briefly, bone marrow cells were obtained from wild type (WT) and Nrf2 KO C57JBL/6 mice and cultured in DMEM medium containing growth factors of 20 ng/ml recombinant M-CSF (Sigma–Aldrich) and 10% FBS at 37°C, 5% CO 2 .…”

Helminth Therapy for Immune-Mediated Inflammatory Diseases: Current and Future Perspectives

“…108 The serine protease inhibitor secreted by Trichinella spiralis can also induce alternative activation of peritoneal macrophages and bone marrow-derived macrophages in mice, and these alternatively activated macrophages can alleviate pathological changes in the colon caused by TNBS. 109 Similarly, serine protease from Trichinella spiralis can induce macrophages to produce IL-10 to inhibit colitis caused by DSS. 110 The Fhecl1 protease of Fasciola hepatica and cathepsin B1 protease of Schistosoma mansoni , members of the cysteine protease family, can degrade endosomal TLR3 receptors of macrophages and inhibit TRIF-dependent signaling pathways to directly suppress the development of the Th1-type immune response.…”