Systemic Delivery Of Anti-integrin αL Antibodies Reduce Early Macrophage Recruitment, Inflammation And Scar Formation In Murine Burn Wounds
Xanthe L. Strudwick1, Damian H. Adams1, Natasha T. Pyne2, Michael S. Samuel2, Rachael Z. Murray3, Allison J. Cowin1.
1Future Industries Institute, University of South Australia, Adelaide SA 5001, Australia, 2Centre for Cancer Biology, University of South Australia, Adelaide SA 5001, Australia, 3Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, 4001, Australia.
Macrophages present in early stages of the repair process play a key role in regulating wound fibrosis and scar formation. Burns are prone to increased macrophage recruitment leading to an excessive inflammatory response associated with elevated fibrosis and scarring. This recruitment relies upon integrins on the surface of monocytes that regulate their migration and extravasation from the circulation into the wound site, where they then differentiate into macrophages. High levels of key immune specific integrin αL, part of the lymphocyte function-associated antigen-1, were found expressed in circulating monocytes purified from the blood of burns patients compared to burn wound associated macrophages, from the same patient (n=7), suggesting a role in monocyte extravasation.
Integrin αL was targeted in mice (n=8) one day post scald burn injury with 50µg intravenous delivery of neutralising antibody.
Burn wound associated macrophages were reduced by 54.7% at day 3 (p=0.030), with levels returning to normal by day 7. The early stage reduction in macrophages led to a concomitant reduction in pro-inflammatory tumour necrosis factor alpha (p=0.030) and pro-scarring transforming growth factor beta (p=0.022) levels. This reduced inflammatory response was associated with reduced alpha smooth muscle actin expression during the proliferative phase of healing (day 7, p=0.016) and an overall trend towards reduced scar formation. Wounds appeared more similar to unwounded skin, with a lower collagen I/III ratio (p=0.048) and improved scar appearance (p=0.041) 28 days following burn injury in mice treated with anti- integrin αL compared to control treated mice.
These results suggest targeted integrin αL therapy reduces macrophage infiltration into burn wounds leading to a reduced early inflammatory response and reduced scar formation following burn injury.
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