From iron sequestration to immune paralysis: A biphasic model of Lipocalin-2 function in sepsis
Abstract
Sepsis is a life-threatening syndrome arising from a dysregulated host response to infection, characterized by a biphasic immune trajectory in which an early hyperinflammatory phase transitions into a prolonged state of immunosuppression. This late phase is dominated by massive apoptotic depletion of lymphocytes, functional exhaustion of monocytes and macrophages, and an inability to mount effective responses against secondary infections, collectively defining immune paralysis. Indeed, most sepsis-related deaths occur during this phase of immune paralysis. Throughout the sepsis response, various pro- and anti-inflammatory mediators are released, particularly cytokines. Among the factors released during sepsis, Lipocalin-2 (Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted innate immune glycoprotein induced during infection as a bacteriostatic mediator that sequesters iron-bound bacterial siderophores, thereby depriving pathogens of a nutrient essential for growth and dissemination. While this early protective function of Lcn2 is well established, accumulating experimental and clinical evidence points to a second, temporally distinct role during the immunosuppressive phase. In murine models of polymicrobial sepsis, Lcn2 expression at both the mRNA and protein levels is uniquely sustained throughout the late phase, in sharp contrast to other inflammatory mediators that rapidly resolve. This persistent expression may drive iron-dependent metabolic stress, activation of intrinsic apoptotic pathways in lymphocytes, and stabilization of macrophage tolerance. In human patients, circulating NGAL correlates with inflammatory cytokines, endothelial activation, and disease severity, and persistently elevated levels associate with adverse outcomes. We propose that Lcn2 may act as a phase-dependent regulator of the septic immune response, serving a protective and antimicrobial role during early infection while potentially contributing to immune dysfunction when its expression is sustained. This dual behavior positions Lcn2 as both a clinically informative biomarker and a candidate target for therapeutic intervention in sepsis.
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BibTeX
@article{cauvi2026from,
title = {{From iron sequestration to immune paralysis: A biphasic model of Lipocalin-2 function in sepsis}},
author = {David M. Cauvi and Antonio De Maio},
journal = {Innate Immunity},
year = {2026},
month = nov,
doi = {10.1177/17534259261506889},
url = {https://doi.org/10.1177/17534259261506889},
note = {CC BY},
}
RIS
TY - JOUR
TI - From iron sequestration to immune paralysis: A biphasic model of Lipocalin-2 function in sepsis
AU - David M. Cauvi
AU - Antonio De Maio
PY - 2026
DA - 2026/11/06
JO - Innate Immunity
DO - 10.1177/17534259261506889
UR - https://doi.org/10.1177/17534259261506889
AB - Sepsis is a life-threatening syndrome arising from a dysregulated host response to infection, characterized by a biphasic immune trajectory in which an early hyperinflammatory phase transitions into a prolonged state of immunosuppression. This late phase is dominated by massive apoptotic depletion of lymphocytes, functional exhaustion of monocytes and macrophages, and an inability to mount effective responses against secondary infections, collectively defining immune paralysis. Indeed, most sepsis-related deaths occur during this phase of immune paralysis. Throughout the sepsis response, various pro- and anti-inflammatory mediators are released, particularly cytokines. Among the factors released during sepsis, Lipocalin-2 (Lcn2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted innate immune glycoprotein induced during infection as a bacteriostatic mediator that sequesters iron-bound bacterial siderophores, thereby depriving pathogens of a nutrient essential for growth and dissemination. While this early protective function of Lcn2 is well established, accumulating experimental and clinical evidence points to a second, temporally distinct role during the immunosuppressive phase. In murine models of polymicrobial sepsis, Lcn2 expression at both the mRNA and protein levels is uniquely sustained throughout the late phase, in sharp contrast to other inflammatory mediators that rapidly resolve. This persistent expression may drive iron-dependent metabolic stress, activation of intrinsic apoptotic pathways in lymphocytes, and stabilization of macrophage tolerance. In human patients, circulating NGAL correlates with inflammatory cytokines, endothelial activation, and disease severity, and persistently elevated levels associate with adverse outcomes. We propose that Lcn2 may act as a phase-dependent regulator of the septic immune response, serving a protective and antimicrobial role during early infection while potentially contributing to immune dysfunction when its expression is sustained. This dual behavior positions Lcn2 as both a clinically informative biomarker and a candidate target for therapeutic intervention in sepsis.
SN - 1753-4267
SN - 1753-4259
ER -