Systemic delivery of anti-integrin alpha L antibodies reduces early macrophage recruitment, inflammation, and scar formation in murine burn wounds

Online Ahead of Print:January 28, 2020Objective: Increased macrophage recruitment in the early stages of wound healing leads 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 differentiate into macrophages. The aim of this study was to determine if inhibiting monocyte extravasation from the circulation into burns would reduce macrophages numbers in burns and lead to reduced inflammation and scar formation. Approach: Scald burns were created on mice and treated with integrin alpha L (αL) function blocking antibody via intravenous delivery day 1 after injury. The effect of inhibiting macrophage recruitment into the burn was assessed using macro- and microscopic wound parameters as well as immunohistochemistry for inflammatory cell markers, cytokines, and collagen deposition. Results: Burn wound-associated macrophages were reduced by 54.7% at day 3 following treatment with integrin αL antibody, with levels returning to normal by day 7. This reduction in macrophages led to a concomitant reduction in inflammatory mediators, including tumor necrosis factor-alpha (TNFα) and Il-10 as well as a reduction in proscarring transforming growth factor beta 1 (TGFβ1). This reduced inflammatory response was also associated with less alpha smooth muscle actin (αSMA) expression and an overall trend toward reduced scar formation with a lower collagen I/III ratio. Innovation: Treatment of burns with integrin αL function blocking antibodies reduces inflammation in burn wounds. Conclusion: These results suggest that reducing macrophage infiltration into burn wounds may lead to a reduced early inflammatory response and less scar formation following burn injury.Xanthe L. Strudwick, Damian H. Adams, Natasha T. Pyne, Michael S. Samuel, Rachael Z. Murray and Allison J. Cowi

ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism

Corrected by: Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism (Nature Cell Biology, (2020), 22, (908)). In the PDF version of this article originally published, a text label was omitted from Fig. 2g. The heading for the images in the right-hand column of Fig. 2g should be “R-PyMT + 4HT”. The error has been corrected in the PDF version of the paper.It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer–microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK–PERK–ATF4–CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.Sarah Theresa Boyle, Valentina Poltavets, Jasreen Kular, Natasha Theresa Pyne, Jarrod John Sandow, Alexander Charles Lewis, Kendelle Joan Murphy, Natasha Kolesnikoff, Paul Andre Bartholomew Moretti, Melinda Nay Tea, Vinay Tergaonkar, Paul Timpson, Stuart Maxwell Pitson, Andrew Ian Webb, Robert John Whitfield, Angel Francisco Lopez, Marina Kochetkova, and Michael Susithiran Samue