(LR-049) Deregulated inflammatory response and immune cell function traps chronic wounds in a suppressed inflammatory state to contribute to inhibition of wound healing

Jelena Marjanovic, PhD; Rivka Stone, MD/PhD; Ivan Jozic, PhD; Jaime Burgess, BS; Harold Brem, MD; Ojirese Momoh, PhD; Hadar Lev-Tov, MD; Robert Kirsner, MD; Maria Morasso, PhD; Irena Pastar, PhD; Marjana Tomic-Canic, PhD

Introduction: Chronic wounds are a life-threatening disease with a high mortality rate and represent a major clinical challenge. Increased inflammation has been regarded as a hallmark of chronic wounds. The current paradigm describes chronic wounds as “stuck in a chronic inflammatory phase” that does not progress, contributing to inhibition of healing. However, this paradigm has been primarily derived from studies comparing chronic wounds to unwounded skin in which several aspects of the inflammatory response are lacking and never triggered. Furthermore, lack of appropriate preclinical models fail to adequately recapitulate human chronic wounds. Moreover, therapeutic targeting of the inflammatory process to curb inflammation in chronic wounds has proven to be clinically unsuccessful.

Methods: To decipher the role of inflammation in chronic wounds, we performed genomic studies by RNA-seq of diabetic foot ulcers (DFUs, n=13) and venous leg ulcers (VLUs, n=11). Location matched human acute wounds (n=8) served as controls obtained three days post-wounding, the peak of inflammatory phase.

Results: We identified transcriptional networks and immune signaling pathways that are suppressed in DFUs and VLUs compared to acute wounds. DFUs revealed TREM1/FOXM1 pathway to be suppressed (p=0.01), contributing to decreased macrophage/neutrophil recruitment and function. Deconvolution of transcriptional data revealed decreased leukocyte populations including pro-inflammatory macrophages (M1) in VLUs and confirmed by immunostainings. Furthermore, chemokine markers and integrin receptors important for immune cell recruitment were suppressed (p=0.001), which was confirmed by qPCR. Diminished inflammatory response was coupled with increased production of cortisol, a potent anti-inflammatory factor and inhibitor of wound healing, in DFUs and VLUs. Overall, we identified an imbalance between pro-inflammatory and anti-inflammatory responses along with impaired function and signaling of inflammatory cells that fail to reach levels of acute healing wounds.

Discussion: We present evidence that describes a paradigm shift demonstrating diminished inflammatory state with the apparent need for a paradigm shift that redefines chronic wounds from “stuck in a chronic inflammatory phase” to the stuck in deregulated inflammatory response that renders them incapable of progressing through the healing process. Our data highlight the clinical relevance by providing the rationale for the failure of several therapies aimed at suppressing inflammation and reveals new therapeutic strategies to stimulate an acute wound-like inflammatory response to shift chronic wounds into acute healing wounds.