Background Helminths immunomodulate the host immune system by secreting proteins to create an inhibitory environment as a strategy for survival in the host. As a bystander effect, this balances the host immune system to reduce hypersensitivity to allergens or autoantigens. Based on this, helminth therapy has been used to treat some allergic or autoimmune diseases. As a tissue-dwelling helminth, Trichinella spiralis infection has been identified to have strong immunomodulatory effects; the effective components in the worm have not yet been identified. Methods The soluble extracts of T. spiralis adult worms and muscle larvae were used to treat airway inflammation before and after an ovalbumin (OVA)-sensitization/challenge in an OVA-induced asthma mouse model. The therapeutic effects were observed by measuring the level of inflammation in the lungs. Results The soluble products derived from T. spiralis parasites, especially from adult worms, were able to ameliorate OVA-induced airway inflammatory responses which were associated with reduced eosinophil infiltration, OVA-specific IgE, Th2 cytokine IL-4, and increased IL-10 and TGF-β. The stimulation of the Treg response may contribute to the alleviated allergic inflammation. Conclusions Trichinella spiralis worm extracts stimulate regulatory cytokines that are associated with reduced allergic airway inflammation. The identification of effective components in the adult worm extracts will be a crucial approach for developing a novel therapeutic for allergic and autoimmune diseases.

Background: Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. Although many studies having confirmed that helminthderived proteins have strong immunomodulatory functions and could treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum-produced cystatin (Sj-Cys) on sepsis-induced cardiac dysfunction. Methods: A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mice. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj-Cys (rSj-Cys). Twelve hours after CLP, the systolic and diastolic functions of the left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera, and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of rSj-Cys, myeloid differentiation factor 88 (MyD88) was determined in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocytes. In addition, the therapeutic effects of rSj-Cys on LPS-induced cardiomyocyte apoptosis were also detected. The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6, and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of rSj-Cys-treated mice. Results: After rSj-Cys treatment, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were significantly alleviated, characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera, and MPO activity in heart tissue. The therapeutic efficacy of rSj-Cys is associated with downregulated pro-inflammatory cytokines (TNF-α and IL-6) and upregulated regulatory inflammatory cytokines (IL-10 and TGF-β), possibly through inhibiting the LPS-MyD88 signal pathway. Conclusions: RSj-Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.

Multi-organ failure caused by the inflammatory cytokine storm induced by severe infection is the major cause of death for sepsis. Sj-Cys is a cysteine protease inhibitor secreted by Schistosoma japonicum with strong immunomodulatory functions on host immune system. Our previous studies have shown that treatment with Sj-Cys recombinant protein (rSj-Cys) attenuated inflammation caused by sepsis. However, the immunological mechanism underlying the immunomodulation of Sj-Cys for regulating inflammatory diseases is not yet known. In this study, we investigated the effect of Sj-Cys on the macrophage M2 polarization and subsequent therapeutic effect on sepsis. The rSj-Cys was expressed in yeast Pichia pastoris. Incubation of mouse bone marrow-derived macrophages (BMDMs) with yeast-expressed rSj-Cys significantly activated the polarization of macrophages to M2 subtype characterized by the expression of F4/80+ CD206+ with the elated secretion of IL-10 and TGF-β. Adoptive transfer of rSj-Cys treated BMDMs to mice with sepsis induced by cecal ligation and puncture (CLP) significantly improved their survival rates and the systemic clinical manifestations of sepsis compared with mice receiving non-treated normal BMDMs. The therapeutic effect of Sj-Cys-induced M2 macrophages on sepsis was also reflected by the reduced pathological damages in organs of heart, lung, liver and kidney and reduced serological levels of tissue damage-related ALT, AST, BUN and Cr, associated with downregulated pro-inflammatory cytokines (IFN-gamma and IL-6) and upregulated regulatory anti-inflammatory cytokines (IL-10 and TGF-β). Our results demonstrated that Sj-Cys is a strong immunomodulatory protein with anti-inflammatory features through activating M2 macrophage polarization. The findings of this study suggested that Sj-Cys itself or Sj-Cys-induced M2 macrophages could be used as therapeutic agents in the treatment of sepsis or other inflammatory diseases.

Background Myocardial dysfunction is one of the most common complications of multiple organ failure in septic shock and significantly increases mortality in patients with sepsis. In spite of many studies have confirmed that helminth-derived proteins have strong immunomodulatory functions and could be used to treat inflammatory diseases, there is no report on the therapeutic effect of Schistosoma japonicum -produced cystatin ( Sj- Cys) on the sepsis-induced cardiac dysfunction. Methods A model of sepsis-induced myocardial injury was established by cecal ligation and puncture (CLP) in mouse. Upon CLP operation, each mouse was intraperitoneally treated with 10 µg of recombinant Sj -Cys (r Sj -Cys). Twelve hours after CLP operation, the systolic and diastolic functions of left ventricular were examined by echocardiography. The levels of myoglobin (Mb), cardiac troponin I (cTnI), N-terminal pro-Brain Natriuretic peptide (NT-proBNP) in sera and the activity of myeloperoxidase (MPO) in cardiac tissues were examined as biomarkers for heart injury. The heart tissue was collected for checking pathological changes, macrophages and pro-inflammatory cytokine levels. To address the signaling pathway involved in the anti-inflammatory effects of r Sj -Cys, myeloid differentiation factor 88 (MyD88) was determined by Western blot in heart tissue of mice with sepsis and LPS-stimulated H9C2 cardiomyocyte cells. In addition, the therapeutic effects of r Sj -Cys on LPS-induced cardiomyocyte apoptosis were also detected in H9C2 cells.The levels of M1 biomarker iNOS and M2 biomarker Arg-1 were detected in heart tissue. The pro-inflammatory cytokines TNF-α and IL-6 and regulatory cytokines IL-10 and TGF-β were measured in sera and their mRNA levels in heart tissue of r Sj -Cys-treated mice. Results After being treated with r Sj -Cys, the sepsis-induced heart malfunction was largely improved. The inflammation and injury of heart tissue were also significantly alleviated characterized as significantly decreased infiltration of inflammatory cells in cardiac tissues and fiber swelling, reduced levels of Mb, cTnI and NT-proBNP in sera and MPO activity in heart tissue. The therapeutic efficacy of r Sj -Cys is associated with down-regulated pro-inflammatory cytokines (TNF-α, IL-6) , as well as the decreased M1 macrophages and increased M2 macrophages, possibly through inhibiting LPS-MyD88 signal pathway. Conclusions Recombinant Sj -Cys significantly reduced sepsis-induced cardiomyopathy and could be considered as be a potential therapeutic agent for the prevention and treatment of sepsis associated cardiac dysfunction.