Abstract
Inflammation after trauma is both critical to normal wound healing and may be highly detrimental when prolonged or unchecked with the potential to impair physiologic healing and promote de novo pathology. Mechanical strain after trauma is associated with impaired wound healing and increased inflammation. The exact mechanisms behind this are not fully elucidated. Neutrophil extracellular traps (NETs), a component of the neutrophil response to trauma, are implicated in a range of pro-inflammatory conditions. In the current study, we evaluated their role in linking movement and inflammation. We found that a link exists between the disruption and amplification of NETs which harbors the potential to regulate the wound's response to mechanical strain, while leaving the initial inflammatory signal necessary for physiologic wound healing intact.
Highlights
Musculoskeletal trauma poses a unique challenge due to the need for early mobilization to facilitate rehabilitation
Single cell analysis of the neutrophil population attracted to the injury site 7 days after injury demonstrated early elevation in mRNA encoding several cytokines previously demonstrated to be associated with neutrophil and monocyte attraction and with NETosis (e.g. Ccl3, Ccl4, Ccr1, Cxcl16, Gpi1, Il1b, Il18, Osm, Tnf ), when compared with non-inflammatory mesenchymal cell populations (Supplemental Data Figures 2A–K)
Our findings suggest a model in which NETosis is propagated and augmented by the physical or chemical disruption of formed Neutrophil extracellular traps (NETs) both in vivo and in vitro
Summary
Musculoskeletal trauma poses a unique challenge due to the need for early mobilization to facilitate rehabilitation. Immobilization or “resting” of an injured joint is often implemented to reduce local inflammation and edema [7,8,9]. The mechanism for this local effect of immobilization remains poorly characterized. Anti-inflammatory therapeutics such as corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) reduce systemic inflammation [10], they do not target pathways specific to the pro-inflammatory effects of mechanical strain; these drugs cause well-recognized adverse effects including poor wound healing, diabetes, hyperlipidemia, and gastrointestinal toxicity [10,11,12]. Identification of specific pathways through which mechanical strain propagates the inflammatory response would expand therapeutic strategies to mitigate acute inflammation, prevent pathologic wound healing, reduce time to rehabilitation, and improve patient recovery. In addition to musculoskeletal trauma, these findings may influence treatment for a broad spectrum of pathologies mediated by mechanical strain [13,14,15]
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