A Trypsin-Sensitive Proteoglycan from the Tapeworm <b><i>Hymenolepis diminuta</i></b> Inhibits Murine Neutrophil Chemotaxis in vitro by Suppressing p38 MAP Kinase Activation

Abstract

It has emerged that neutrophils can play important roles in the host response following infection with helminth parasites. Mice infected with the tapeworm, Hymenolepis diminuta, are protected from some inflammatory conditions, accompanied by reduced neutrophil tissue infiltration. Thus, the ability of a phosphate-buffered saline-soluble extract of the worm (H. diminuta extract [HdE]) was tested for (1) its ability to activate murine neutrophils (Ca²⁺ mobilization, reactive oxygen species (ROS) and cytokine production); and (2) affect neutrophil chemotaxis in vitro to the penta-peptide, WKYMVm, the chemokine, KC, and leukotriene B₄. HdE was not cytotoxic to neutrophils, elicited a Ca²⁺ response and ROS, but not, cytokine (KC, interleukin-10, tumour necrosis factor-α) generation. HdE is not a chemotactic stimulus for murine neutrophils. However, a heat- and trypsin-sensitive, acid-insensitive proteoglycan (sensitive to sodium metaperiodate) in the HdE significantly reduced neutrophil chemotaxis towards WKYMVm or KC, but not LTB₄. The latter suggested that the HdE interfered with p38 mitogen-activated protein kinase signalling, which is important in WKYMVm chemotaxis. Corroborating this, immunoblotting revealed reduced phosphorylated p38, and the downstream signal heat-shock protein-27, in protein extracts from HdE + WkYMVm treated cells compared to those exposed to the penta-peptide only. We speculate that HdE can be used to modify the outcome of neutrophilic disease and that purification of the bioactive proteoglycan(s) from the extract could be used as a template to design immunomodulatory drugs targeting neutrophils.

Characterization of Tapeworm Metabolites and Their Reported Biological Activities

“…These immunoregulatory strategies protect gastrointestinal tapeworms (such as D. caninum ) from being ejected by the immune response but also provide protection to the host (only when present in moderate numbers) against gastrointestinal inflammatory diseases that result from a dysfunctional immune system. For example, the high molecular weight extracts of the rat tapeworm, Hymenolepis diminuta , has been shown to protect mice against experimental colitis and arthritis [7,8].…”

Enteric tuft cells coordinate timely expulsion of the tapeworm Hymenolepis diminuta from the murine host by coordinating local but not systemic immunity

“…brasiliensis [ 49 ] and in vitro analysis has shown that an extract of H . diminuta directly affects migration of both of these cell types [ 50 , 51 ]. Complementing previous publications that show increased Foxp3 mRNA expression in infected mice [ 29 , 52 ], Foxp3 + T cells were increased in the Peyer’s patches of infected Pou2f3 +/+ .…”

Tryptase and Exogenous Trypsin: Mechanisms and Ophthalmic Applications

“…[29][30][31] Furthermore, tryptase-activated neutrophils have traditionally been viewed as a frontline defence against microbial infections, carrying proteases that can destroy invaders but might also cause considerable collateral damage to the host. 32 Once activated, neutrophils release soluble factors and granules into the extracellular environment both to facilitate their translocation, and to promote fixation or killing of pathogens. 33 Neutrophil degranulation has been associated with the pathogenesis of dry eye, as has upregulated release of various soluble inflammatory mediators including MMP-9, lysozyme and tryptase.…”