Abstract
Cutaneous exposure to the DNA alkylating class of chemotherapeutic agents including nitrogen mustard (NM) leads to both skin injury and systemic inflammation. Circulating myeloid subsets recruited to the skin act to further exacerbate local tissue damage while interfering with the wound healing process. We demonstrate herein that intravenous delivery of poly(lactic-co-glycolic acid) immune-modifying nanoparticles (PLGA-IMPs) shortly after NM exposure restricts accumulation of macrophages and inflammatory monocytes at the injury site, resulting in attenuated skin pathology. Furthermore, PLGA-IMPs induce an early influx and local enrichment of Foxp3+ regulatory T cells (Treg) in the skin lesions critical for the suppression of myeloid cell-pro-inflammatory responses via induction of IL-10 and TGF-β in the cutaneous milieu. Functional depletion of CD4+ Tregs ablates the efficacy of PLGA-IMPs accompanied by a loss of local accumulation of anti-inflammatory cytokines essential for wound healing. Thus, in severe skin trauma, PLGA-IMPs may have therapeutic potential via modulation of inflammatory myeloid cells and regulatory T lymphocytes.
| Original language | English (US) |
|---|---|
| Article number | 37 |
| Journal | npj Regenerative Medicine |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
We are grateful for access to de-identified tissue from the published clinical trial and to the subjects who had participated in the original study. We also thank the Northwestern University Skin Biology and Diseases Resource-Cased Center (SBDRC, P30 AR075049) for their help with tissue processing, the Robert H. Lurie Comprehensive Cancer Center Flow Core for providing the instrumentation and expertise for the flow cytometric analysis, and the Center for Advanced Molecular Imaging (CAMI, NCI CCSG P30 CA060553) for providing access to imaging modalities. Research reported in this publication was supported by the National Institutes of Health Chemical Countermeasures Research Program (CCRP) executed by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Institutes of Health Office of the Director (NIH OD) under award number U54AR079795 (K.Q.L., S.D.M., I.C.L., and N.C.G.) and U01AR071168 (K.Q.L. and S.D.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Biomedical Engineering
- Developmental Biology
- Cell Biology