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Prostaglandin E2 Induces Oncostatin M Expression in Human Chronic Wound Macrophages through Axl Receptor Tyrosine Kinase Pathway

Research Scholar

Kasturi Ganesh Barki, Surgery - Davis Heart & Lung Research Institute (India)
Chandan Sen, Co-Reseacher
Gayle Gordillo, Co-Reseacher
Narasimham L. Parinandi, Co-Researcher
Savita Khanna, Co-Researcher
Amitava Das, Co-Researcher
Ryan Dickerson, Co-Researcher
Sashwati Roy, Faculty Mentor


Kasturi Ganesh Barki is a native of Karnataka, India.  She pursued her medical education at Mahadevappa Rampure Medical College and was awarded with a Bachelor of Medicine, Bachelor of Surgery degree from Gulbarga University prior to her acceptance as a postdoctoral researcher in the Department of Surgery at the Wexner Medical Center at The Ohio State University, in Sashwati Roy's laboratory. Under Roy's mentorship, Ganesh Barki's research focuses on studying the role of macrophages in chronic wound inflammation, and she recently published her work in the Journal of Immunology.

What is the issue or problem addressed in your research?

Macrophages play a key role in wound repair such that both inadequate inflammatory responses to wounding as well as unresolved inflammation compromise wound closure. Monocytes and macrophages are highly plastic cells that differentiate into mf based on cues at the specific wound microenvironment. The functional fate of monocytes recruited to the wound-site is governed by the specific properties of the wound microenvironment.Current understandings on wound inflammation is primarily based on the study of blood monocyte-derived macrophage (MDM), cells that have never been exposed to the wound microenvironment.

What methodology did you use in your research?

We sought to develop an approach to collect functionally intact mf from clinically presented chronic wounds. Outcomes from such cell were compared in a pair-matched manner with the peripheral monocyte-derived mf of the same individual. Such studies identified oncostatin M (OSM) as a key differentially expressed cytokine abundantly produced by human chronic wound mf Both PGE2 and its metabolite 13,14-dihydro-15-keto-PGE2 (PGE-M) were abundant in wound fluid and induced OSM in wound-site mf. We sought to characterize the mechanism underlying OSM induction in wound mf as well as understand the significance of OSM in wound inflammation.

For the experiments, the THP-1 cells differentiated to mf using phorbol-12-myristate-13-acetate (PMA, 20 ng/ml, 48h) were used. In addition, the macrophages isolated from human chronic wounds were also used.

Treatment of human THP-1 cell-derived mf with PGE2 or PGE-M caused dose-dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human mf, PGE2 phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analog demonstrating interplay between the cAMP and RTK pathways. PGE2–dependent Axl phosphorylation led to AP-1 transactivation which is directly implicated in inducible expression of OSM. Treatment of human mf or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNFa and IL-1b. OSM treatment also improved wound closure during the early inflammatory phase of healing.

What are the purpose/rationale and implications of your research?

Finally, the observation that OSM functions as an anti-inflammatory agent at the wound site introduces a novel element in the overall biology addressing the control of wound inflammation.