Inflammation and Organ Injury the Role of Substance P and Its Receptors

Abstract

Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide with a robust effect on inflammation. The proinflammatory effects of SP are achieved by activating its functional receptors, namely the neurokinin 1 receptor (NK1R) receptor and mas-related G protein-coupled receptors X member 2 (MRGPRX2) and its murine homolog MRGPRB2. Upon activation, the receptors further signal to several cellular signaling pathways involved in the onset, development, and progression of inflammation. Therefore, excessive SP–NK1R or SP–MRGPRX2/B2 signals have been implicated in the pathogenesis of inflammation-associated organ injury. In this review, we summarize our current knowledge of SP and its receptors and the emerging roles of the SP–NK1R system and the SP–MRGPRX2/B2 system in inflammation and injury in multiple organs resulting from different pathologies. We also briefly discuss the prospect of developing a therapeutic strategy for inflammatory organ injury by disrupting the proinflammatory actions of SP via pharmacological intervention.

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

“…These alterations show that the dysregulation of intracellular iron accumulation and lipid peroxidation in the liver and lungs in mice arises following CLP-surgery-induced sepsis, indicating that ferroptosis was increased in these tissues in mice with sepsis. Given the roles of the SP-NK1R axis in promoting acute inflammatory response [ 5 , 41 , 42 ] and COX-2 expression [ 27 , 28 , 29 ] in inflammation-related pathological circumstances, it is worth probing into the impact of this axis on the profile of ferroptosis in sepsis. Notably, this study showed that these increases in the concentration of iron and MDA in the liver and lungs in mice following CLP-surgery-induced sepsis were reduced by either the deletion of the Tac1 gene, the pharmacological blockage of NK1R, or the combination of these two methods.…”

“…Substance P (SP) is an undecapeptide encoded by the Tac1 gene in rodents [ 4 ]. It has been implicated in diverse biological processes and pathological settings, predominantly by activating its functional receptor, named neurokinin 1 receptor (NK1R) [ 5 ]. Increased SP-NK1R signalling has been shown to contribute to aberrant systemic inflammatory response, leading to acute inflammatory injury in multiple organs, including the liver, lungs, and kidney in sepsis [ 5 , 6 , 7 ].…”