Helminth Induced Suppression of Macrophage Activation Is Correlated with Inhibition of Calcium Channel Activity

Abstract

Helminth parasites cause persistent infections in humans and yet many infected individuals are asymptomatic. Neurocysticercosis (NCC), a disease of the central nervous system (CNS) caused by the cestode Taenia solium, has a long asymptomatic phase correlated with an absence of brain inflammation. However, the mechanisms of immune suppression remain poorly understood. Here we report that murine NCC displays a lack of cell surface maturation markers in infiltrating myeloid cells. Furthermore, soluble parasite ligands (PL) failed to induce maturation of macrophages, and inhibited TLR-induced inflammatory cytokine production. Importantly, PL treatment abolished both LPS and thapsigargin-induced store operated Ca2+ entry (SOCE). Moreover, electrophysiological recordings demonstrated PL-mediated inhibition of LPS or Tg-induced currents that were TRPC1-dependent. Concomitantly STIM1-TRPC1 complex was also impaired that was essential for SOCE and sustained Ca2+ entry. Likewise loss of SOCE due to PL further inhibited NFkB activation. Overall, our results indicate that the negative regulation of agonist induced Ca2+ signaling pathway by parasite ligands may be a novel immune suppressive mechanism to block the initiation of the inflammatory response associated with helminth infections.

Extracellular calcium elicits feedforward regulation of the Toll-like receptor-triggered innate immune response

“…Previous studies have suggested that increased intracellular calcium plays important roles in mediating the TLR-triggered immune response. [35][36][37][38][39][40][41][42][43][44][45][46][47] In most studies, attention has been paid to intracellular calcium mobilization. However, TLRs may trigger calcium release from the ER and then STIM-ORAImediated calcium entry.…”

Immunopathology in Taenia solium neurocysticercosis

“…A long asymptomatic period, marked by the absence of local inflammation, usually follows the parasite establishment in the CNS . When parasite and/or host signals trigger the inflammatory response, symptoms commence with the ensuing damage of both peripheral and central cysticerci in pigs and humans .…”

“TRP inflammation” relationship in cardiovascular system

“…These findings favor the view that activation of TRPC1 is required for the host defense against bacterial infections through the TLR4-TRPC1-PKCα signaling pathway, but its excessive activity may lead to exacerbation of inflammation [32]. A similar but in-opposite-direction involvement of TRPC1-mediated Ca 2+ entry in TLR-mediated inflammation has been demonstrated in microglia and macrophages from m i c e i n t r a c r a n i a l l y i n o c u l a t e d w i t h a h e l m i n t h Mesocestoides corti [33,34]; it has been known that humans infected with a related helminth cestode Taenia solium have immunosuppressive rather than inflammatory responses in the asymptomatic phase after the infection. Experiments using It should be noted that appropriate operation of autophagy is essential to suppress the caspase-1 activity, which would prevent the production of inflammatory cytokine (IL-1β and IL-18).…”

“…One of the factors known to activate NF-κB is an elevation in [Ca 2+ ] i [100,101]. There are several papers linking Ca 2+ -permeable TRP channels to NF-κB-mediated inflammatory reactions; suppression of TRPC1-mediated Ca 2+ entry inhibited NF-κB activation, which is associated with immunosuppressive mechanism in helminth infections [34]; pharmacological inhibition of TRPM7 channel suggested its involvement in LPS-induced EC migration via the TLR-NF-κB signaling [37]; endotoxininduced lung injury involves TLR4-mediated NF-κB activation in a manner dependent on TRPC6-mediated Ca 2+ entry [21].…”