HIF-1α is required to differentiate the neonatal Macrophage protein secretome from adults
Amanda Becker1, Mallory Filipp2, Connor Lantz2
1Department of Pediatrics, Division of Critical Care Medicine, Northwestern Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611 USA.
Insights
Neonatal macrophages promote regeneration and protect against stress, while adult macrophages drive inflammation and pathogen killing. These age-dependent immune responses are regulated by hypoxia-inducible factor-1α (HIF-1α).
Area of Science:
- Immunology
- Cell Biology
- Aging Research
Background:
- Immune responses to stress, particularly involving macrophages, differ significantly between neonatal and adult individuals.
- Macrophage stress responses involve recognizing hypoxia and pathogen-associated molecular patterns (PAMPs), but age-specific differences are not well understood.
- Neonatal macrophages are linked to tissue regeneration, whereas adult macrophages are associated with scarring and inflammation.
Purpose of the Study:
- To investigate age-defined differences in macrophage secreted proteins following exposure to hypoxia and PAMPs.
- To uncover age-specific signatures in macrophage secretomes and understand their role in stress response.
- To explore the potential of targeting these age-dependent responses for immune calibration.
Main Methods:
- Interrogation of secreted proteomes from neonatal versus adult macrophages using non-biased mass spectrometry.
- Exposure of macrophages to hypoxia and lipopolysaccharide (LPS), a prototypical PAMP.
- Analysis of age-specific protein signatures and their functional implications.
Main Results:
- Identified distinct age-specific secretome signatures in macrophages responding to hypoxia and LPS.
- Neonatal macrophages exhibited an anti-inflammatory, regenerative phenotype, protected against apoptosis and oxidative stress, dependent on hypoxia-inducible transcription factor-1α (HIF-1α).
- Adult macrophages displayed a pro-inflammatory, glycolytic phenotype associated with pathogen killing.
Conclusions:
- Macrophage responses to stress are fundamentally divergent based on age and are HIF-1α dependent.
- Neonatal macrophages support regeneration, while adult macrophages focus on pathogen clearance.
- These findings offer potential targets for modulating innate immune responses during stress and inflammation.
Abstract:
The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages secreted proteins most consistent with an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1α (HIF-1α). In contrast, adult macrophages secreted proteins consistent with a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1α dependent macrophage responses that may be targeted to calibrate the innate immune response during stress and inflammation.
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