Molecular and preclinical evaluation of PCT/CRLR-Antagonism as a novel strategy to treat sepsis.
Orthopaedics, Traumatology, Reconstructive Surgery
Final Report Abstract
Sepsis represents a severe global health problem and is the most common cause of death in non-cardiac intensive care units. Procalcitonin (PCT) has emerged as the most sensitive and specific biomarker of bacterial sepsis. Despite the widespread clinical use of PCT as a biomarker, there is still uncertainty about a biological function of PCT during septic shock. In this project, we provide evidence that PCT functions as a mediator in sepsis, worsening disease outcomes in mice with experimental sepsis. Mechanistic studies show that PCT favors M1-macrophage polarization and potentiates pro-inflammatory immune responses. Likewise, PCT inhibits the migration of activated macrophages, which is not only relevant in sepsis, but also bone resorption during treatment with intermittent teriparatide. Moreover, we show that PCT exerts its harmful effect on murine sepsis outcomes through the Calcitonin Receptor-Like Receptor (CRLR), a G-protein coupled receptor also involved in the pathophysiology of migraine through binding calcitonin gene-related peptide (CGRP). In this regard, treatment of septic mice with the prototype of novel anti-migraine drugs, olcegepant, improved survival rates in pre-clinical mouse models of septic shock. While PCT/CRLR antagonism also limits pro-resorptive responses in a large animal model of polymicrobial sepsis, it decreases survival due to deleterious cardiovascular effects, most likely involving CGRP signaling. Together, our findings clearly establish a pro-inflammatory role of PCT in bacterial sepsis, which however requires alternative means of pharmacological targeting in order to be of clinical use.
Publications
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Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor. Crit Care Med. 2021 Jan 1;49(1):e41-e52
Baranowsky A, Appelt J, Kleber C, Lange T, Ludewig P, Jahn D, Pandey P, Keller D, Rose T, Schetler D, Braumüller S, Huber-Lang M, Tsitsilonis S, Yorgan T, Frosch KH, Amling M, Schinke T, Keller J
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Procalcitonin is expressed in osteoblasts and limits bone resorption through inhibition of macrophage migration during intermittent PTH treatment. Bone Res. 2022 Jan 27;10(1):9
Baranowsky A, Jahn D, Jiang S, Yorgan T, Ludewig P, Appelt J, Albrecht KK, Otto E, Knapstein P, Donat A, Winneberger J, Rosenthal L, Köhli P, Erdmann C, Fuchs M, Frosch KH, Tsitsilonis S, Amling M, Schinke T, Keller J
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Systemic calcitonin gene-related peptide receptor antagonism decreases survival in a porcine model of polymicrobial sepsis: blinded randomised controlled trial. Br J Anaesth. 2022 May;128(5):864-873
Messerer DAC, Datzmann T, Baranowsky A, Peschel L, Hoffmann A, Gröger M, Amling M, Wepler M, Nussbaum BL, Jiang S, Knapstein P, Donat A, Calzia E, Radermacher P, Keller J
