Macrophages represent key cellular drivers of chronic joint inflammation in rheumatoid arthritis (RA). Recently, synovial fibroblasts have also emerged as active players in this disease. Interestingly, fibroblasts and other mesenchymal stromal cells impart immunosuppressive activity in a wide-range of tissues. Here we wish to explore how rampant inflammation persists in RA despite a massive outgrowth of fibroblasts. Our preliminary evidence suggests that RA synovial fibroblasts indeed promote anti-inflammatory pathways in macrophages. In the context of the RA inflammatory milieu, we propose this results in a mixed pro-inflammatory and wound- healing macrophage phenotype. As wound-healing macrophages support fibroblast function, we are interested in whether induction of wound-healing responses in RA macrophages ultimately feeds back to support fibroblast expansion and invasiveness. This ultimately may establish a perpetual crosstalk cycle, which promotes survival of both cell types, inflammation and tissue damage. RA afflicts over 1 million Americans. Current therapies target pro-inflammatory macrophage responses. Here we propose that macrophage wound healing responses may also represent critical therapeutic targets, as these responses may promote fibroblast-mediated RA pathogenesis. The candidate obtained a PhD in immunology from Columbia University and pursued postdoctoral fellowship at Rockefeller University in epigenetics and cell signaling. She is now motivated to apply her rigorous basic science training towards establishing an academic career in clinically relevant research focused on the pathophysiology of RA. In order to meet this goal, she will conduct research in the laboratory of Lionel Ivashkiv at Hospital for Special Surgery, where she will gain significant experience working with human tissue and a deeper understanding of rheumatic diseases from the clinical perspective. Dr. Ivashkiv is a board certified rheumatologist, an expert in cytokine-mediated inflammatory responses and has trained scientists who now hold faculty positions.

Public Health Relevance

Rheumatoid arthritis (RA) afflicts over 1 million American adults, causing chronic joint inflammation and pain. Although several therapies exist, a deeper knowledge of this disease is required to improve the lives of patients living with this chronic illness. Here we aim to further our understanding of RA and identify novel therapeutic targets by studying how cells in the RA joint function cooperatively to elicit inflammation and tissue damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AR066063-01
Application #
8678347
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mao, Su-Yau
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$105,414
Indirect Cost
$7,808
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Donlin, Laura T; Jayatilleke, Arundathi; Giannopoulou, Eugenia G et al. (2014) Modulation of TNF-induced macrophage polarization by synovial fibroblasts. J Immunol 193:2373-83