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

Fever is a common thermoregulatory manifestation in systemic inflammation, which can be triggered by different stimuli, such as infection, head trauma, and neurological disorders. In experimental animals, fever is often induced by administration of bacterial lipopolysaccharide (LPS), and it is associated with the release of a wide range of proinflammatory mediators, including also substance P (SP). 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.

We studied the fever response to LPS in mice with the Tacr1 gene, i.e. the gene encoding the NK1 receptor, homozygously present (Tacr1^+/+) or absent (Tacr1^−/−). In the absence of the NK1 receptor, LPS-induced fever was attenuated starting from the early phase (from ~40 min). On the contrary, we found no difference in the febrigenic effect of prostaglandin (PG) E₂ 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).

Figure 1. Simplified schematic of the mechanisms in endotoxin fever, highlighting the interaction between SP signaling and the cytokine-COX-2-PGE₂ axis based on the study in focus [1] (see text for explanation). AA: arachidonic acid; COX-2: cyclooxygenase-2; EP3: prostaglandin EP3 receptor; LPS: lipopolysaccharide; MnPO: median preoptic nuclues; mPGES-1: microsomal PGE₂ synthase-1; NK1: neurokinin-1; PGE₂: prostaglandin E₂; POA: preoptic area; TLR4: Toll-like receptor 4.

When a microorganism crosses the physical barriers (e.g. in the skin, or in the gastrointestinal or respiratory tract) of the host, the innate immune response is initiated. LPS is recognized by the Toll-like receptor 4 (TLR4), which is expressed in immune cells, including monocytes and macrophages. TLR4 activation results in the translocation of NF-κB into the nucleus, which mounts the gene expression and synthesis of various inflammatory mediators, including pyrogenic cytokines, such as interleukin-1, -6, and tumor necrosis factor-α. Besides cytokine production, the arachidonic acid (AA) cascade is also activated in leukocytes, thereby yielding considerable amounts of lipid-derived mediators. Of these, PGE₂, the end-product of the COX-2-microsomal PGE₂ synthase-1 (mPGES-1) pathway, is the key mediator of fever (Figure 1) [2].

The initial phase of fever depends mainly on PGE₂ produced in peripheral organs, likely in lung and liver macrophages, while the later phases of fever are mediated by PGE₂ synthetized within the blood-brain barrier. In the central nervous system, PGE₂ interacts with EP3-expressing neurons in the median preoptic nucleus (MnPO) of the preoptic area (POA) of the hypothalamus, thereby, triggering the activation of autonomic cold defense thermoeffectors (e.g. skin vasoconstriction and nonshivering thermogenesis), and leading to the induction of fever (Figure 1) [2].

The potential roles of SP and its receptors cover a wide range in systemic inflammation and in its common clinical manifestation, sepsis. NK1 receptors are expressed in leukocytes, in different peripheral tissues (e.g. vessels, intestines, lungs, liver), and in the brain [3]. 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]. 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. 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 in increased PGE₂ production, and in the initiation of the fever response [1] (Figure 1). Whether the activity of other enzymes downstream or upstream COX-2 (e.g. phospholipase A₂, monoacylglycerol lipase, and mPGES-1) is also affected by the SP-NK1 receptor pathway remains subject for further research.

The importance of the changes in body temperature, viz., fever and hypothermia, in systemic inflammation is well established [2]. Fever is associated with decreased, whereas hypothermia with increased rate of death in sepsis [2,4], though it has to be noted that body temperature per se does not serve as the cause of the outcome, but instead, it is an indicator of the actual coping strategy of the host, and, as such, it gives information about the severity of the disease [4]. Similar to body temperature, an association between SP levels and mortality was also observed in septic patients [5]. The risk of death was lower in patients who had persistently higher levels of SP starting from the time of diagnosis of sepsis, whereas non-survivors had sustained low serum levels of SP [5]. Based on the results of the study in focus [1], the similarity between the predictive roles of SP and body temperature on the mortality rate in sepsis can be explained: SP signaling is involved in the development of fever, hence an elevated SP level also means higher PGE₂ production, and, therefore, a more pronounced fever response. Due to their causative relationship, it is evident that increased serum SP concentration and elevated body temperature both predict lower risk of death in sepsis, as previously known about each of them separately [4,5].

Due to the better understanding of the interaction between SP signaling and the cytokine-COX-2-PGE₂ axis, the findings of the highlighted study [1], in theory, also raise the possibility of the application of NK1 receptor antagonists as antipyretic drugs. Some NK1 receptor antagonists are already used in clinical practice as antiemetic drugs, however, their use in systemic inflammation to reduce fever is doubtful, as the anti-inflammatory efficacy of different NK1 antagonists could not be firmly confirmed in human studies. Moreover, even if the use of NK1 antagonists as antipyretics is confirmed in clinical trials, the question of when to use these drugs still remains, since their inappropriate application may counteract the beneficial impact of higher SP levels and elevated body temperature on the outcome of the disease in systemic inflammation.