Substance P signaling contributes to granuloma formation in Taenia crassiceps infection, a murine model of cysticercosis

Abstract

Cysticercosis is an infection with larval cysts of the cestode Taenia solium. Through pathways that are incompletely understood, dying parasites initiate a granulomatous reaction that, in the brain, causes seizures. Substance P (SP), a neuropeptide involved in pain-transmission, contributes to inflammation and previously was detected in granulomas associated with dead T. crassiceps cysts. To determine if SP contributes to granuloma formation, we measured granuloma-size and levels of IL-1beta, TNF-alpha, and IL-6 within granulomas in T. crassiceps-infected wild type (WT) mice and mice deficient in SP-precursor (SPP) or the SP-receptor (neurokinin 1, NK1). Granuloma volumes of infected SPP- and NK1-knockout mice were reduced by 31 and 36%, respectively, compared to WT mice (P < .05 for both) and produced up to 5-fold less IL-1beta, TNF-alpha, and IL-6 protein. Thus, SP signaling contributes to granuloma development and proinflammatory cytokine production in T. crassiceps infection and suggests a potential role for this mediator in human cystercercosis.

Figure 1

(a) Representative granuloma derived from infected WT, SPP-knockout, and NK1-knockout mice (white bar = 1 mm). (b) Volumes of granulomas derived from Taenia crassiceps infected, wild type (n = 2) versus SPP-knockout (n = 4) and NK1-knockout mice (n = 3). Data presented are mean ± SD; *P < 05, size of infected, SPP-knockout derived granulomas versus WT derived granulomas, ^†P < .05, size of infected, NK1-knockout derived granulomas versus WT derived granulomas.

Figure 2

Quantitative levels of IL-1β in granulomas derived from Taenia crassiceps infected, WT (n = 15), SPP-knockout mice (n = 6) and NK1-knockout mice (n = 9). Data presented are mean ± SEM; *P < 05, IL-1β levels in infected, SPP-knockout derived granulomas versus WT derived granulomas; ^†P < .05, IL-1β levels in infected, NK1-knockout derived granulomas versus WT derived granulomas.

Figure 3

Quantitative levels of TNF-α in granulomas derived from Taenia crassiceps infected, WT (n = 13), SPP-knockout mice (n = 4), and NK1-knockout mice (n = 9). Data presented are mean ± SEM; *P < 05, TNF-α levels in infected, SPP-knockout derived granulomas versus WT derived granulomas.

Figure 4

Quantitative levels of IL-6 in granulomas derived from Taenia crassiceps infected, WT (n = 12), SPP-knockout mice (n = 6), and NK1-knockout mice (n = 9). Data presented are mean ± SEM; *P < 05, IL-6 levels in infected, SPP-knockout derived granulomas versus WT derived granulomas, ^†P < .05, IL-6 levels in infected, NK1-knockout derived granulomas versus WT derived granulomas.