# Thrombocytopoiesis in Diabetes: Role of Damage Associated Molecular Patterns

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $540,859

## Abstract

Project Summary
Patients with both types of diabetes mellitus have greater thrombotic risk than non-diabetic subjects. The exact
reasons are unclear, but is partly due to increased number of reticulated platelets (RPs) and pro-inflammatory
leukocytes. We recently reported that elevated blood glucose in type 1 diabetes (T1D) increases the number of
RPs and platelet-leukocyte aggregates (PLAs). Mechanistically, we found that enhanced glycolytic stress in
neutrophils promote secretion of certain alarmins that in turn bind to their receptor (RAGE) on Kupffer cells (KCs)
to produce thrombopoietin (TPO) from hepatocytes. The released TPO interact with its receptor, cMPL on
hematopoietic stem cells and platlelet progenitors to enhance the formation of RPs from the bone marrow (BM).
Surprisingly, unlike in T1D, the TPO levels in models of obesity/ type 2 diabetes (T2D) and humans were
unaltered, yet, the number of KCs in the liver and RPs in the blood were elevated. Normalizing blood glucose
did not reverse these changes implying that pathways that regulate thrombopoiesis in T2D are different. Further
interrogations led to the identification of enhanced NLRP3 inflammasome signaling in macrophages (fat and
liver) as a source of thrombopoietic cytokines (i.e., IL-1β, IL-1α and CCL5). These cytokines may interact with
megakaryocytes (MK) in a TPO-independent manner to promote thrombopoiesis. Based on these findings, we
hypothesize that, “the NLRP3 inflammasome signaling in macrophages of fat and/or liver drives thrombopoiesis
via TPO-independent mechanisms in obesity/ T2D”. We will test the hypothesis using 2 specific aims in a mouse
model of diet-induced obesity (DIO)/ T2D. Aim 1 will define the integral role of NLRP3 inflammasome-Gasdermin
D signaling in promoting thrombopoiesis. In this Aim, first, we will identify the major cellular source of
inflammasome signaling using flow cytometry and scRNA seq. Second, we will study the functional role of
inflammasome-GSDMD signaling in driving thrombopoiesis by employing pharmacological and, various global,
conditional and cell-specific Nlrp3 or Gasdermin D (Gsdmd) deletion strategies. For each intervention, the effect
of Nlrp3/ Gsdmd inhibition on downstream signaling mediators and its overall impact on thrombopoiesis will be
studied. Aim 2 will define the TPO-independent pathways of thrombopoiesis downstream of inflammasome. In
this aim, first, we will study the role of a MK-biased vWF+ HSC subset in driving thrombopoiesis mediated by IL-
1β, IL-1α and/ or CCL5. Strategies include global or MK-specific deletion of Il1r1, Ccr5 and cMpl. These studies
will reveal if the products of inflammasome are capable of driving thrombopoiesis independent of TPO-cMPL by
directly interacting with MKs.

## Key facts

- **NIH application ID:** 10972793
- **Project number:** 7R01HL137799-06
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Prabhakara Reddy Nagareddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $540,859
- **Award type:** 7
- **Project period:** 2023-11-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10972793

## Citation

> US National Institutes of Health, RePORTER application 10972793, Thrombocytopoiesis in Diabetes: Role of Damage Associated Molecular Patterns (7R01HL137799-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10972793. Licensed CC0.

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