Abstract
BackgroundNeurocysticercosis (NCC) is a disease of the central nervous system (CNS) caused by the cestode Taenia solium. The infection exhibits a long asymptomatic phase, typically lasting 3 to 5 years, before the onset of the symptomatic phase. The severity of the symptoms is thought to be associated with the intensity of the inflammatory response elicited by the degenerating parasite. In contrast, the asymptomatic phase shows an absence of brain inflammation, which is presumably due to immunosuppressive effects of the live parasites. However, the host factors and/or pathways involved in inhibiting inflammation remain largely unknown. Recently, using an animal model of NCC in which mice were intracranially inoculated with a related helminth parasite, Mesocestoides corti, we reported that Toll-like receptor (TLR)-associated signaling contributes to the development of the inflammatory response. As microglia shape the initial innate immune response in the CNS, we hypothesized that the negative regulation of a TLR-induced inflammatory pathway in microglia may be a novel helminth-associated immunosuppressive mechanism in NCC.Methods and resultsHere we report that helminth soluble factors (HSFs) from Mesocestoides corti inhibited TLR ligation-induced production of inflammatory cytokines in primary microglia. This was correlated with an inhibition of TLR-initiated upregulation of both phosphorylation and acetylation of the nuclear factor κB (NF-κB) p65 subunit, as well as phosphorylation of JNK and ERK1/2. As Ca2+ influx due to store-operated Ca2+ entry (SOCE) has been implicated in induction of downstream signaling, we tested the inhibitory effect of HSFs on agonist-induced Ca2+ influx and specific Ca2+ channel activation. We discovered that HSFs abolished the lipopolysaccharide (LPS)- or thapsigargin (Tg)-induced increase in intracellular Ca2+ accumulation by blocking the ER store release and SOCE. Moreover, electrophysiological recordings demonstrated HSF-mediated inhibition of LPS- or Tg-induced SOCE currents through both TRPC1 and ORAI1 Ca2+ channels on plasma membrane. This was correlated with a decrease in the TRPC1-STIM1 and ORAI1-STIM1 clustering at the plasma membrane that is essential for sustained Ca2+ entry through these channels.ConclusionInhibition of TRPC1 and ORAI1 Ca2+ channel-mediated activation of NF-κB and MAPK pathways in microglia is likely a novel helminth-induced immunosuppressive mechanism that controls initiation of inflammatory response in the CNS.
Highlights
Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system (CNS) caused by the cestode Taenia solium
Our results indicate that Helminth secretory or soluble factor (HSF) downregulate the agonist-induced inflammatory response and the activation of store-operated Ca2+ entry (SOCE) channels (transient receptor potential channel 1 (TRPC1) and ORAI Ca2+ release-activated Ca2+ modulator 1 (ORAI1)) and associated signaling pathways in microglia
Coexposure with HSFs led to complete inhibition of Toll-like receptor (TLR) ligand-induced secretion of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) cytokines by microglia (Figure 1A and 1B)
Summary
Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system (CNS) caused by the cestode Taenia solium. One possible explanation could be that viable cysticerci induce immunosuppressive effects to evade the host immune response Loss of these effects (when the parasite dies) could lead to uncontrolled hyperinflammatory responses that contribute to tissue pathology and clinical signs and symptoms such as severe headaches, epilepsy, intracranial hypertension, focal deficit and cognitive impairment [2,5,6]. As microglia shape the initial innate immune response in the CNS, we hypothesized that the negative regulation of a TLR-induced inflammatory pathway in microglia may be a novel helminth-associated immunosuppressive mechanism in NCC
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