# Early life adversity and biological sex developmentally heighten the mast cell proinflammatory phenotype by modulating its cholesterol metabolism

> **NIH NIH F31** · MICHIGAN STATE UNIVERSITY · 2024 · $29,155

## Abstract

PROJECT SUMMARY
Early life adversity (ELA) induces long-lasting chronic low-grade inflammation and increases the risk for
chronic inflammatory diseases (CIDs) like obesity, diabetes, and atherosclerosis later in life. Current literature
on the adult immune phenotype following ELA has shown hyperinflammatory leukocyte signaling as a driver of
chronic inflammation. However, the intracellular mechanisms through which ELA alters definitive
hematopoiesis and developmentally programs leukocyte inflammatory signaling remain unclear. Mast cells
(MCs) are well-established orchestrators of immune responses and leukocyte recruiters, and their heightened
activity is unsurprisingly characteristic of ELA associated diseases. Using murine and porcine models of ELA,
we have previously demonstrated the MC as an effector cell of the inflammatory and behavioral responses to
acute and chronic stress. We used the murine ELA model of neonatal maternal separation with early weaning
(NMS) to perform a preliminary characterization of the ELA-associated, MC inflammatory phenotype. Bone
marrow resident hematopoietic stem cells (HSCs) and progenitors from adult NMS and normally handled (NH)
control mice of both sexes were differentiated in culture into primary bone marrow derived MCs (BMMCs). In
comparison to BMMCs from NH mice of the same sex, BMMCs from NMS mice exhibited greater IgE-mediated
release of dense core secretory granule (DCSG) proinflammatory mediators and LPS- and IL33-induced
release of de novo synthesized cytokines. Our preliminary data revealed that BMMCs from NMS mice
exhibited upregulation of cholesterol-related genes, with greater pathway upregulation in NMS females.
Further, inhibition of cholesterol biosynthesis coincided with decreased DCSG mediators. The primary
objective of this proposal is to define the mechanisms through which ELA alters MC programming, specifically
focusing on cholesterol metabolism, to developmentally heighten the MC inflammatory phenotype and
enhance host susceptibility to disease. Our primary hypothesis is that ELA modulates the long-term MC
inflammatory phenotype and MC programming through the upregulation of intracellular cholesterol metabolism,
which is critical for increased granulogenesis and MC proinflammatory activity. To test this hypothesis, we will
utilize primary BMMC cultures and tissue MCs from NMS and NH mice of both sexes as in vitro and in vivo
models, respectively, of the functional and developmental effects of ELA on immunity. Aim 1 will investigate the
impact of ELA on MCp and MC cholesterol metabolism and their link to granulogenesis, while Aim 2 will
examine the role of cholesterol metabolism and granulogenesis in the ELA-heightened MC inflammatory
phenotype. These experiments will define intracellular cholesterol metabolism as a target mechanism driving
the long-term effects of ELA on MC programming and MC inflammatory phenotype. This proposed research
has far-reaching implications for understanding how ...

## Key facts

- **NIH application ID:** 10904388
- **Project number:** 1F31AI183710-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Janelle LeMon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $29,155
- **Award type:** 1
- **Project period:** 2024-07-25 → 2025-05-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904388

## Citation

> US National Institutes of Health, RePORTER application 10904388, Early life adversity and biological sex developmentally heighten the mast cell proinflammatory phenotype by modulating its cholesterol metabolism (1F31AI183710-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10904388. Licensed CC0.

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