Suppressing the Substance P-NK1R Signalling Protects Mice against Sepsis-Associated Acute Inflammatory Injury and Ferroptosis in the Liver and Lungs

Abstract

Substance P (SP), encoded by the TAC1/Tac1 gene, acts as a significant mediator in dysregulated systemic inflammatory response and associated organ injury in sepsis by activating the neurokinin-1 receptor (NK1R). This study investigated the impact of SP-NK1R signaling on ferroptosis in the liver and lungs of mice with sepsis. Sepsis was induced by caecal ligation puncture (CLP) surgery in mice. The SP-NK1R signaling was suppressed by Tac1 gene deletion, NK1R blockade, and a combination of these two approaches. The physiological conditions of mice were recorded. The profile of the SP-NK1R cascade, inflammatory response, ferroptosis, and tissue histology were investigated in the liver and lungs. Several manifestations of sepsis occurred in Tac1+/+ mice during the development of sepsis. Notably, hypothermia became significant four hours after the induction of sepsis. In the liver and lungs of mice subjected to CLP surgery, the concentrations of SP and NK1R were upregulated. Additionally, the concentrations of pro-inflammatory mediators, including cytokines (IL-1β, IL-6, and TNF-α) and chemokines (MCP-1 and MIP-2), were increased. Moreover, ferroptosis was elevated, as evidenced by increased concentrations of iron and MDA and reduced concentrations of GSH, Nrf2, and Gpx4. Suppressing the SP-NK1R cascade significantly mitigated CLP-surgery-induced alterations in mice. Importantly, these three approaches used to suppress SP-NK1R signaling showed similar effects on protecting mice against sepsis. In conclusion, increased SP-mediated acute inflammatory response and injury in the liver and lungs in mice with CLP-surgery-induced sepsis was associated with elevated ferroptosis. The detrimental effect of SP on sepsis was predominantly mediated by NK1R. Therefore, the suppression of increased SP-NK1R signaling and ferroptosis may be a promising adjuvant therapeutic candidate for sepsis and associated acute liver and lung injury.

Ferroptosis inhibitors: past, present and future

“…Additionally, ferroptosis inhibitors like Fer-1 and pioglitazone have been shown to reverse AKI damage in a mouse model by targeting ferroptosis, offering promising avenues for AKI treatment ( Hosohata et al, 2022 ). Acute liver injury is another condition with high clinical mortality rates, and recent studies have highlighted the potential of Nrf2 activation in mitigating liver injury ( Zhu et al, 2024 ). Furthermore, research by Yamada et al, 2020 indicated that upregulation of ferroptosis markers (iron ions, lipid peroxide levels) exacerbated liver injury in hepatic IRI models, but treatment with ferroptosis inhibitors like Fer-1 significantly reduced injury severity.…”

Substance P Promotes Leukocyte Infiltration in the Liver and Lungs of Mice with Sepsis: A Key Role for Adhesion Molecules on Vascular Endothelial Cells

“…The mechanism leading to the dysregulated inflammatory response during sepsis remains poorly understood [ 4 ]. Substance P (SP), encoded by the tachykinin 1 ( Tac1 ) gene in rodents [ 5 ], has been demonstrated to be an important mediator contributing to the dysregulation of the acute inflammatory response in the liver and lungs of mice with sepsis [ 6 ]. The pro-inflammatory actions of SP in sepsis-associated acute liver and lung injury are mainly mediated by neurokinin-1 receptor (NK1R) [ 6 ].…”

“…Substance P (SP), encoded by the tachykinin 1 ( Tac1 ) gene in rodents [ 5 ], has been demonstrated to be an important mediator contributing to the dysregulation of the acute inflammatory response in the liver and lungs of mice with sepsis [ 6 ]. The pro-inflammatory actions of SP in sepsis-associated acute liver and lung injury are mainly mediated by neurokinin-1 receptor (NK1R) [ 6 ]. However, the precise mechanism leading to the detrimental effects of SP on sepsis remains to be investigated.…”

“…Recently, we have shown that increased SP-NK1R signalling contributes to the upregulation of leukocyte infiltration and acute inflammatory injury in the liver and lungs of mice with sepsis induced by caecal ligation and puncture (CLP) surgery [ 6 ]. The recruitment of leukocytes to the sites of injury from the bloodstream is a complex process that involves many (patho)physiological mechanisms [ 7 , 8 , 9 , 10 , 11 ].…”

“…The deletion of the Tac1 gene has been shown to protect mice from sepsis-related liver sinusoidal endothelial cell damage, linking the abnormal biosynthesis of SP to the dysfunction of vascular endothelial cells in the liver in sepsis [ 26 ]. The increased SP-NK1R signalling has been implicated in the upregulated production of cytokines, including TNF-α and IL-1β, in the liver and lungs of mice with sepsis induced by CLP surgery [ 6 ]. These studies collectively identified the possible involvement of SP in the activation of vascular endothelial cells in these tissues of mice with CLP surgery-induced sepsis by activating NK1R.…”