Project Details
Projekt
Targeting nociceptors to modulate neutrophil mobilization and homing in sepsis
Subject Area
Anaesthesiology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 414847370
Sepsis is a life-threatening complication on the ICU with high mortality rates. Sepsis is defined by an overshooting immune activation and microvascular dysfunction in response to pathogens leading to compromised organ dysfunction and failure. Neither the overshooting immune response nor the dysfunction of the vasculature can currently be therapeutically addressed by clinicians when caring for septic patients on the ICU. In the first funding period, we identified that procalcitonin, a sepsis biomarker associated with adverse sepsis outcome, affects vascular integrity by binding to its receptor on the endothelium, the calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein 1 (RAMP1). Antagonizing procalcitonin’s activation or its action on the CRLR/RAMP1 prevented sepsis-induced vascular barrier dysfunction and ameliorated capillary leakage in patients with post-operative systemic inflammation. The CRLR/RAMP1 complex is also present on immune cells and has recently been shown to be involved in signaling of nociceptors in the bone marrow during bacterial infection. Our preliminary data suggests that CRLR/RAMP1 is primarily expressed on immature neutrophils that have been associated with limited anti-microbial activity, tissue-damaging properties and adverse outcome in septic patients. In addition, septic mice deficient in the nociceptor transient receptor potential vanilloid 1 (TRPV1) exhibited reduced expansion of neutrophil counts during sepsis and limited sepsis-induced tissue injury. In the second funding period, the applicants will now team up to dissect how sepsis-induced activation of TRPV1 expressed on afferent nerves in the bone marrow modulates CRLR/RAMP1 activity on immune cells by triggering the release of the CRLR/RAMP1 agonist calcitonin gene-related peptide (CGRP) in the bone marrow niche. In murine and porcine models of polymicrobial sepsis we will dissect how this TRPV1 signaling axis modulates neutrophil phenotype, egress into the circulation and their homing to target tissues and whether antagonizing CRLR/RAMP1 is a means to shift circulating neutrophil phenotypes towards a tissue-protective phenotype during sepsis. We will also characterize how endogenous hyperprocalcitonemia during sepsis affects TRPV1-CRLR/RAMP1 signaling in septic patients and evaluate whether elevated levels of procalcitonin can identify patients particularly exhibiting neutrophil immaturity and impaired function associated with worse clinical outcome. Together with our collaboration partners in the clinical research unit 342 our goal with this proposal is to identify the TRPV1-CRLR/RAMP1 axis as a target to tailor sepsis-induced immune responses and protect the vasculature translating into improved organ function and outcome of patients with sepsis.
DFG Programme
Clinical Research Units
Subproject of
KFO 342:
Organ Dysfuncion During Systemic Inflammation
