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Inflammation Controls Susceptibility of Immune-Experienced Mice to Sepsis
Journal article   Open access   Peer reviewed

Inflammation Controls Susceptibility of Immune-Experienced Mice to Sepsis

Roger R Berton, Isaac J Jensen, John T Harty, Thomas S Griffith and Vladimir P Badovinac
ImmunoHorizons, Vol.6(7), pp.528-542
07/25/2022
DOI: 10.4049/immunohorizons.2200050
PMCID: PMC9650784
PMID: 35878936
url
https://doi.org/10.4049/immunohorizons.2200050View
Published (Version of record) Open Access

Abstract

Sepsis, an amplified immune response to systemic infection that leads to life-threatening organ dysfunction, affects >125,000 people/ day worldwide with 20% mortality. Modest therapeutic progress for sepsis has been made, in part because of the lack of therapeutic translatability between mouse-based experimental models and humans. One potential reason for this difference stems from the extensive use of immunologically naive specific pathogen-free mice in preclinical research. To address this issue, we used sequential infections with well-defined BSL-2 pathogens to establish a novel immune-experienced mouse model (specific pathogen experienced [SPexp]) to determine the extent to which immunological experience and/or inflammation influences the host capacity to respond to subsequent infections, including sepsis. Consistent with their immunological experience, SPexp inbred or outbred mice had significant changes in the composition and activation status of multiple leukocyte populations known to influence the severity of cecal ligation and puncture–induced sepsis. Importantly, by varying the timing of sepsis induction, we found the level of basal inflammation controls sepsis-induced morbidity and mortality in SPexp mice. In addition, although a beneficial role of NK cells in sepsis was recently demonstrated in specific pathogen-free mice, NK cell depletion before cecal ligation and puncture induction in SPexp mice lead to diminished mortality, suggesting NK cells may have beneficial or detrimental roles in the response to septic insult dependent on host immune status. Thus, data highlight the importance of utilizing immune-experienced models for preclinical studies to interrogate the cellular/molecular mechanism(s) that could be therapeutically exploited during severe and dysregulated infection-induced inflammatory responses, such as sepsis.

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