# Trained innate immunity and periodontitis-associated comorbidities

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $373,750

## Abstract

Project Summary
Periodontal disease (PD) is a prevalent oral inflammatory condition that is epidemiologically associated with
systemic disorders (comorbidities), such as, cardiovascular disease, rheumatoid arthritis, and type-2 diabetes.
An independent association between PD and comorbidities remains even after adjustment for confounders. A
possible factor contributing to this independent association is that PD can cause low-grade systemic
inflammation, which may in turn influence comorbidities. The relationship between PD and systemic comorbidities
is bidirectional in that systemic diseases can also promote susceptibility to PD. However, there is no known
unifying causal mechanism that can explain how PD affects and is affected by comorbidities. To mechanistically
explain the reciprocal association between PD and comorbid conditions, a novel hypothesis is proposed based
on the recent concept that systemic inflammatory stimuli can cause epigenetic rewiring of hematopoietic stem
and progenitor cells (HSPCs) in the bone marrow, which enables these cells to give rise to ‘trained’ myeloid cells
that can respond more strongly to future stimuli. This concept represents a form of innate immune memory and
is known as ‘trained innate immunity’ (TII). TII can be protective in infections but potentially detrimental, hence
maladaptive, in inflammatory disorders. Thus, given that chronic inflammatory diseases are – in large part –
driven by the action of inflammatory myeloid cells, inflammation-driven transcriptomic and epigenetic alterations
in their bone marrow progenitors are likely to influence the initiation or the progression of different chronic
inflammatory disorders that emerge as comorbidities. This project involves investigation of the comorbidity of PD
with another inflammatory bone loss disorder, rheumatoid arthritis. The overarching hypothesis is that
maladaptive TII constitutes a mechanistic basis for the comorbid connection of PD and arthritis, which are studied
using validated preclinical models, ligature-induced PD (LIP) and collagen antibody-induced arthritis (CAIA),
respectively. The objective of Aim 1 is to show that inflammation-adapted HSPCs in the bone marrow mediates
the comorbid association of PD and inflammatory arthritis. That the proposed maladaptive effect is mediated by
inflammation-adapted (‘trained’) HSPCs will be tested by bone marrow transplantation experiments. Aim 2 was
designed to investigate whether experimental PD induces transmissible epigenetic modifications in bone marrow
progenitors towards a maladaptive inflammatory phenotype that underlies the development of inflammatory
comorbidities. Further studies are proposed to show that interleukin-1β acts on HSPCs to mediate LIP-induced
trained myelopoiesis and increased disease activity (Aim 3). If successful, this project will provide a unifying
network for and mechanistic insights into the interconnection of inflammatory comorbidities and maladaptive TII
in the bone mar...

## Key facts

- **NIH application ID:** 10328655
- **Project number:** 1R01DE031206-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Georgios Hajishengallis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $373,750
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328655

## Citation

> US National Institutes of Health, RePORTER application 10328655, Trained innate immunity and periodontitis-associated comorbidities (1R01DE031206-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328655. Licensed CC0.

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