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Published on: July 16, 2021
Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53:
Robert A Mitchell1, Hong Liao, Jason Chesney
1Picower Institute for Medical Research, New York, NY 11030, USA. rmitchell@picower.edu
Abstract:
The importance of the macrophage in innate immunity is underscored by its secretion of an array of powerful immunoregulatory and effector molecules. We report herein that macrophage migration inhibitory factor (MIF), a product of activated macrophages, sustains macrophage survival and function by suppressing activation-induced, p53-dependent apoptosis. Endotoxin administration to MIF(-/-) mice results in decreased macrophage viability, decreased proinflammatory function, and increased apoptosis when compared with wild-type controls. Moreover, inhibition of p53 in endotoxin-treated, MIF-deficient macrophages suppresses enhanced apoptosis and restores proinflammatory function. MIF inhibits p53 activity in macrophages via an autocrine regulatory pathway, resulting in a decrease in cellular p53 accumulation and subsequent function. Inhibition of p53 by MIF coincides with the induction of arachidonic acid metabolism and cyclooxygenase-2 (Cox-2) expression, which is required for MIF regulation of p53. MIF's effect on macrophage viability and survival provides a previously unrecognized mechanism to explain its critical proinflammatory action in conditions such as sepsis, and suggests new approaches for the modulation of innate immune responses.
Insights
Macrophage migration inhibitory factor (MIF) prevents programmed cell death (apoptosis) in macrophages, crucial for innate immunity. This finding reveals a new way to control immune responses in conditions like sepsis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Medicine
Background:
- Macrophages are key players in innate immunity, producing critical immunoregulatory molecules.
- Macrophage migration inhibitory factor (MIF) is a secreted product of activated macrophages.
- Understanding macrophage survival mechanisms is vital for innate immune response modulation.
Purpose of the Study:
- To investigate the role of MIF in regulating macrophage survival and function.
- To elucidate the mechanism by which MIF suppresses apoptosis.
- To explore MIF's impact on innate immunity, particularly in the context of sepsis.
Main Methods:
- Utilized MIF-deficient (MIF(-/-)) and wild-type mice.
- Administered endotoxin to induce immune responses.
- Assessed macrophage viability, apoptosis, proinflammatory function, p53 activity, and cyclooxygenase-2 (Cox-2) expression.
Main Results:
- MIF(-/-) mice exhibited decreased macrophage viability, reduced proinflammatory function, and increased apoptosis post-endotoxin challenge compared to wild-type.
- Inhibition of p53 in MIF-deficient macrophages restored proinflammatory function and reduced apoptosis.
- MIF suppresses p53 activity via an autocrine pathway involving arachidonic acid metabolism and Cox-2 induction.
Conclusions:
- MIF sustains macrophage survival and function by inhibiting p53-dependent apoptosis.
- This mechanism highlights MIF's critical role in innate immunity and inflammation, such as in sepsis.
- Findings suggest novel therapeutic strategies for modulating innate immune responses by targeting MIF and p53 pathways.
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