The Neurokinin-1 Receptor Contributes to the Early Phase of Lipopolysaccharide-Induced Fever via Stimulation of Peripheral Cyclooxygenase-2 Protein Expression in Mice

Abstract

Neurokinin (NK) signaling is involved in various inflammatory processes. A common manifestation of systemic inflammation is fever, which is usually induced in animal models with the administration of bacterial lipopolysaccharide (LPS). A role for the NK1 receptor was shown in LPS-induced fever, but the underlying mechanisms of how the NK1 receptor contributes to febrile response, especially in the early phase, have remained unknown. We administered LPS (120 µg/kg, intraperitoneally) to mice with the Tacr1 gene, i.e., the gene encoding the NK1 receptor, either present (Tacr1+/+) or absent (Tacr1−/−) and measured their thermoregulatory responses, serum cytokine levels, tissue cyclooxygenase-2 (COX-2) expression, and prostaglandin (PG) E2 concentration. We found that the LPS-induced febrile response was attenuated in Tacr1−/− compared to their Tacr1+/+ littermates starting from 40 min postinfusion. The febrigenic effect of intracerebroventricularly administered PGE2 was not suppressed in the Tacr1−/− mice. Serum concentration of pyrogenic cytokines did not differ between Tacr1−/− and Tacr1+/+ at 40 min post-LPS infusion. Administration of LPS resulted in amplification of COX-2 mRNA expression in the lungs, liver, and brain of the mice, which was statistically indistinguishable between the genotypes. In contrast, the LPS-induced augmentation of COX-2 protein expression was attenuated in the lungs and tended to be suppressed in the liver of Tacr1−/− mice compared with Tacr1+/+ mice. The Tacr1+/+ mice responded to LPS with a significant surge of PGE2 production in the lungs, whereas Tacr1−/− mice did not. In conclusion, the NK1 receptor is necessary for normal fever genesis. Our results suggest that the NK1 receptor contributes to the early phase of LPS-induced fever by enhancing COX-2 protein expression in the periphery. These findings advance the understanding of the crosstalk between NK signaling and the “cytokine-COX-2-prostaglandin E2” axis in systemic inflammation, thereby open up the possibilities for new therapeutic approaches.

The interaction between neurokinin-1 receptors and cyclooxygenase-2 in fever genesis

“…On the contrary, we found no difference in the febrigenic effect of prostaglandin (PG) E 2 administered into the brain between Tacr1 −/− and Tacr1 +/+ mice. At 40 minutes after LPS administration, serum concentrations of pyrogenic cytokines and COX-2 mRNA expression in the lungs, liver, and brain did not differ between the genotypes, whereas COX-2 protein expression was lower in the lungs and, to a lesser extent, in the liver of Tacr1 −/− mice than in their Tacr1 +/+ littermates [1]. These results show that the NK1 receptor is involved in fever genesis through the facilitation of COX-2 protein expression in peripheral LPS-processing organs such as the lungs and the liver (Figure 1).…”

“…As discussed in the highlighted study [1], NK1 receptors are expressed in macrophages and granulocytes, and the SP-NK1 receptor pathway can trigger the activation and trafficking of these cells, as well as, the upregulation of COX-2 and the production of proinflammatory mediators. It is suggested that SP-induced activation of NK1 receptors on immune cells exacerbates systemic inflammation via recruitment of leukocytes and induction of inflammatory mediator expression [1,3]. Indeed, in septic and aseptic (LPS) animal models of systemic inflammation, the levels of SP were elevated in the lungs and the liver [3], i.e.…”

“…Activation of immune cells, release of inflammatory mediators, vasodilation and edema formation, regulation of apoptosis and bacterial translocation in the gut, as well as, a possible role in lung and liver injury can be all associated with SP signaling in sepsis [3]. As discussed in the highlighted study [1], NK1 receptors are expressed in macrophages and granulocytes, and the SP-NK1 receptor pathway can trigger the activation and trafficking of these cells, as well as, the upregulation of COX-2 and the production of proinflammatory mediators. It is suggested that SP-induced activation of NK1 receptors on immune cells exacerbates systemic inflammation via recruitment of leukocytes and induction of inflammatory mediator expression [1,3].…”

“…The role of SP signaling was sought for long in inflammatory processes, yet its involvement in the induction of systemic inflammation-associated fever has remained unclarified. In our recent study [1], we aimed at identifying the receptorial and molecular mechanisms of the SP-neurokinin (NK)-1 receptor system that are involved in the development of LPS fever.…”

“…in the organs which harbor the peripheral macrophages that trigger fever [2]. The study in focus [1] suggests that the activation of NK1 receptors in these hepatic and pulmonary macrophages contributes to the augmentation of COX-2 protein expression, thereby, resulting Figure 1. Simplified schematic of the mechanisms in endotoxin fever, highlighting the interaction between SP signaling and the cytokine-COX-2-PGE 2 axis based on the study in focus [1] (see text for explanation).…”