# Immunomodulation by splenic megakaryocytes and platelets in sepsis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $621,176

## Abstract

Project Summary
Sepsis is a dysregulated host response to infection that culminates in organ failure leading to millions of deaths
worldwide each year with an increasing incidence as the population ages. There is a fundamental lack of
understanding of the complex host immune response in sepsis that has limited the development of targeted
therapeutics for which there are none beyond antibiotics and supportive care measures. At its core, there is
substantial immunopathology in sepsis with contributions from an overly exuberant immune response and
ineffective pathogen clearance. We and others have studied the critical role of platelets in immune responses
during acute infections, including the role of the lung in extramedullary platelet biogenesis. In this application,
we will explore the role of the spleen, a central immune organ, in extramedullary megakaryopoiesis and platelet
production in sepsis. Based on preliminary data, we hypothesize that the spleen co-opts a significant role in
platelet biogenesis during sepsis and that the platelets produced from the spleen are immunomodulatory and
important in host defense. In Aim 1, we will utilize a mouse model of peritonitis and polymicrobial sepsis resulting
in thrombocytopenia to understand the mechanics of ‘stressed’ platelet biogenesis in this setting. We will study
the role of adrenergic-dependent hematopoietic progenitor mobilization from the bone marrow during sepsis and
the niche-promoting factors that regulate this process. In Aim 2, we will interrogate the engraftment of circulating
hematopoietic progenitors in the spleen, their maturation into megakaryocytes, and the mediators (SCF,
CXCL12, IL-3) regulating this process. Using state-of-the-art techniques such as intravital imaging and lineage
tracing enabled by splenic transplantation, we will test the hypothesis that the spleen significantly contributes to
platelet biogenesis during sepsis. In Aim 3, we will use novel methods of single-cell RNA sequencing of platelets
to test for platelet heterogeneity during homeostasis and sepsis in mice and humans. Within this aim, we will
test a novel cellular therapy for sepsis by transfusing immune-skewed platelets into septic mice and testing for
therapeutic benefit. In summary, these studies will produce paradigm-shifting knowledge on the role of the
spleen in extramedullary megakaryopoiesis and platelet production and the importance of platelet driven
immunity, which will be foundational in the design of new therapeutic approaches to treat sepsis.

## Key facts

- **NIH application ID:** 10521976
- **Project number:** 1R01AI165919-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** MARK ROBERTS LOONEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $621,176
- **Award type:** 1
- **Project period:** 2022-06-07 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521976

## Citation

> US National Institutes of Health, RePORTER application 10521976, Immunomodulation by splenic megakaryocytes and platelets in sepsis (1R01AI165919-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10521976. Licensed CC0.

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