Absence of the SP/SP receptor circuitry in the substance P-precursor knockout mice or SP receptor, neurokinin (NK)1 knockout mice leads to an inhibited cytokine response in granulomas associated with murine Taenia crassiceps infection

Abstract

Neurocysticercosis, caused by the cestode Taenia solium, is the most common parasitic infection of the human central nervous system that leads to seizures. Taenia crassiceps cysticercosis in mice is an experimental model for Taenia solium cysticercosis. Similar to the human infection, live parasites cause little or no granulomatous inflammation. Dying parasites initiate a granulomatous reaction. The neuropeptide, substance P (SP), stimulates T-helper (TH) 1 cytokine production. In the current studies, we determined whether absence of SP/SP receptor circuitry in the SP-precursor, preprotachykinin, knockout or SP-receptor, neurokinin (NK) 1, knockout mice affected granuloma cytokine production. We hence compared the levels of Th1 cytokines interleukin (IL)-2 and interferon (IFN)-gamma, and levels of Th2/immunoregulatory cytokines IL-4 and IL-10, by enzyme-linked immunosorbent assay in T. crassiceps-induced granulomas derived from infected C57BL/6 wild type (WT) versus SP-precursor knockout and NK1 knockout mice. We found that mean levels of IL-2, IFN-gamma, IL-4, and IL-10 in infected WT-derived granulomas were significantly higher than those of granulomas derived from infected SP-precursor knockout or the NK1 receptor (NKIR)knockout mice. Levels of Th2/immunoregulatory cytokines, IL-4 and IL-10 were higher in early stage granulomas (histologically-staged on basis of evidence of parasite remnants) versus late stage granulomas (no parasite-remnants) of both knockouts, whereas the reverse was noted in WT-derived granulomas. These study established that the absence of an SP/SP receptor circuitry in the SP precursor knockout mice or NK1 receptor knockout mice led to an inhibited cytokine response.

Figure 1

Quantitative levels of Th1 cytokine (IL-2) in (A) granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IL-2 levels in infected, SP-Precursor knockout-derived granulomas versus wild type-derived granulomas, †P< .05, IL-2 levels in infected, NK1 knockout-derived granulomas versus wild type-derived granulomas. (B) Early versus late granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IL-2 levels in infected, early stage versus late stage NK1 knockout derived granulomas.

Figure 2

Quantitative levels of Th1 cytokine (IFN-γ) in (A) granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IFN-γ levels in infected, SP-Precursor knockout-derived granulomas versus wild type-derived granulomas, †P< .05, IFN-γ levels in infected, NK1 knockout-derived granulomas versus wild type-derived granulomas. (B) Early versus late granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IFN-γ levels in infected, early stage versus late stage NK1 knockout-derived granulomas.

Figure 3

Quantitative levels of IL-10 in (A) granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IL-10 levels in infected, SP-Precursor knockout-derived granulomas versus wild type-derived granulomas, †P< .05, IL-10 levels in infected, NK1 knockout-derived granulomas versus wild type-derived granulomas. (B) Early versus late granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IL-10 levels in infected, early stage versus late stage NK1 knockout-derived granulomas.

Figure 4

Quantitative levels of Th2 cytokine (IL-4) in (A) granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice. *P< 05, IL-4 levels in infected, SP-Precursor knockout-derived granulomas versus wild type-derived granulomas, †P< .05, IL-4 levels in infected, NK1 knockout-derived granulomas versus wild type-derived granulomas. (B) Early versus late granulomas derived from Taenia crassiceps infected, wild type versus SP-Precursor knockout and NK1 receptor knockout mice., *P< 05, IL-4 levels in infected, early stage versus late stage SP-Precursor knockout-derived granulomas, †P< .05, IL-4 levels in infected, early stage versus late stage NK1 knockout-derived granulomas.