AbstractCutaneous 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.

摘要皮肤暴露于DNA烷化类化学治疗剂（包括氮芥（NM））会导致皮肤损伤和全身炎症。募集到皮肤的循环骨髓亚群进一步加剧局部组织损伤，同时干扰伤口愈合过程。

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.

我们在此证明，在NM暴露后不久静脉内递送聚（乳酸-共-乙醇酸）免疫修饰纳米颗粒（PLGA-IMP）限制了巨噬细胞和炎性单核细胞在损伤部位的积累，导致皮肤病理减弱。此外，PLGA-IMPs在皮肤损伤中诱导Foxp3+调节性T细胞（Treg）的早期流入和局部富集，这对于通过在皮肤环境中诱导IL-10和TGF-β来抑制骨髓细胞促炎反应至关重要。

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..

CD4+Tregs的功能性消耗消除了PLGA-IMP的功效，伴随着伤口愈合所必需的抗炎细胞因子的局部积累的丧失。因此，在严重的皮肤创伤中，PLGA-IMP可能通过调节炎性骨髓细胞和调节性T淋巴细胞而具有治疗潜力。。

IntroductionBeing the largest organ in the body, the skin is commonly exposed to numerous environmental insults and works with immune processes to resolve acute injury1. Circulating innate immune cells respond to injury-induced chemokines and danger signals by infiltrating damaged tissue to clear debris and initiate tissue repair1.

引言作为体内最大的器官，皮肤通常会受到许多环境污染，并与免疫过程一起解决急性损伤1。循环先天免疫细胞通过浸润受损组织清除碎片并启动组织修复来响应损伤诱导的趋化因子和危险信号1。

However, chemokines and inflammatory cytokines produced by activated inflammatory cells, often lead to bystander tissue damage resulting in amplified immune-mediated pathology2.Nitrogen mustard (NM) was the first chemotherapeutic agent discovered in 1942 for the treatment of Hodgkin’s lymphoma and other hematologic cancers3,4.

然而，由活化的炎性细胞产生的趋化因子和炎性细胞因子经常导致旁观者组织损伤，导致免疫介导的病理学扩增2。氮芥（NM）是1942年发现的第一种用于治疗霍奇金淋巴瘤和其他血液学癌症的化学治疗剂3,4。

Along with its numerous derivatives, this class of alkylating agents bind to and crosslink DNA and are frequently used in cancer therapy5. However, drug-induced toxicities are common and often necessitate treatment cessation. NM treatment for skin lymphoma (mycosis fungoides) can result in severe dermatitis and blister formation6.

这类烷基化剂与其众多衍生物一起与DNA结合并交联，经常用于癌症治疗5。然而，药物引起的毒性很常见，通常需要停止治疗。NM治疗皮肤淋巴瘤（蕈样肉芽肿）可导致严重的皮炎和水疱形成6。

Based on historical accounts of victims exposed to the infamous, related sulfur-containing compound, mustard gas, these cytotoxic effects can cause severe injury and death. We and others have shown that the damage resulting from exposure to alkylating agents is not solely attributable to the “1st hit” direct cytotoxicity of the chemical agent7,8,9.

根据受害者接触臭名昭著的含硫化合物芥子气的历史记录，这些细胞毒性作用可能导致严重的伤害和死亡。我们和其他人已经表明，暴露于烷化剂所造成的损害不仅仅归因于化学试剂的“第一次打击”直接细胞毒性7,8,9。

Damaged keratinocytes in the epidermal barrier release high levels of TNF-α, iNOS, ROS, chemokines and proteolytic enzymes creating a highly pro-inflammatory milieu7,10,11,12,13,14. Subsequent recruitment of innate immune cells, specifically inflammatory monocytes and macrophages, to the inflamed site represents an important “2nd hit” that further exacerbates tissue damage7,10,11,12,13,14.In prior studies, we demonstrated that clodronate-mediated ma.

表皮屏障中受损的角质形成细胞释放高水平的TNF-α，iNOS，ROS，趋化因子和蛋白水解酶，形成高度促炎的环境7,10,11,12,13,14。随后将先天免疫细胞，特别是炎性单核细胞和巨噬细胞募集到发炎部位代表了一个重要的“第二次打击”，进一步加剧了组织损伤7,10,11,12,13,14。在先前的研究中，我们证明了氯膦酸盐介导的ma。

Data availability

数据可用性

All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Bulk RNA-seq data are deposited to Gene Expression Omnibus (GEO) accession number GSE218810.

本研究期间生成或分析的所有数据均包含在本文[及其补充信息文件]中。大量RNA-seq数据保存到Gene Expression Omnibus（GEO）登录号GSE218810。

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Download referencesAcknowledgementsWe 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.

下载参考文献致谢我们非常感谢从已发表的临床试验中获得去识别的组织以及参与原始研究的受试者。我们还要感谢西北大学皮肤生物学和疾病资源案例中心（SBDRC，P30 AR075049）在组织处理方面的帮助，RobertH。

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.

Lurie综合癌症中心Flow Core为流式细胞仪分析提供仪器和专业知识，高级分子成像中心（CAMI，NCI CCSG P30 CA060553）提供成像模式。本出版物中报道的研究得到了美国国立卫生研究院化学对策研究计划（CCRP）的支持，该计划由美国国家过敏与传染病研究所（NIAID），美国国家关节炎和肌肉骨骼与皮肤病研究所（NIAMS）以及美国国立卫生研究院主任办公室（NIH OD）执行，奖项编号为U54AR079795（K.Q.L.，S.D.M.，I.C.L。和N.C.G。）和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.Author informationAuthor notesThese authors contributed equally: Ummiye V.

和S.D.M.）。内容完全由作者负责，不一定代表美国国立卫生研究院的官方观点。资助者在研究设计，数据收集，数据分析和解释或撰写本手稿方面没有发挥任何作用。作者信息作者注意到这些作者做出了同样的贡献：Ummiye V。

Onay, Dan Xu.These authors jointly supervised this work: Stephen D. Miller, Kurt Q. Lu.Authors and AffiliationsDepartment of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USAUmmiye V. Onay, Dauren Biyashev, Spencer T. Evans, Michael M. Demczuk, I. Caroline Le Poole, Stephen D.

Onay，Dan Xu。这些作者共同监督了这项工作：Stephen D.Miller，Kurt Q.Lu。作者和附属机构西北大学范伯格医学院皮肤科，伊利诺伊州芝加哥，USAUmmiye V.Onay，Dauren Biyashev，Spencer T.Evans，Michael M.Demczuk，I。卡罗琳·勒·普尔（CarolineLePoole），斯蒂芬·德（StephenD。

Miller & Kurt Q. LuDepartment od Microbiology-Immuno.

Miller＆Kurt Q.LuDepartment od微生物学免疫。

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PubMed Google ScholarContributionsThis work was conceptualized by K.Q.L. and S.D.M. Methodology was determined and study investigation by U.V.O., D.X., D.B., S.E., M.M.D., T.N., J.P., S.B., S.D.M., and K.Q.L. Visualization of results was performed by U.V.O., D.X., and S.E. Funding was acquired by K.Q.L.

PubMed谷歌学术贡献这项工作由K.Q.L.和S.D.M.概念化。方法论由U.V.O.，D.X.，D.B.，S.E.，M.M.D.，T.N.，J.P.，S.B.，S.D.M.和K.Q.L.确定，研究调查由U.V.O.，D.X.进行，S.E.资助由K.Q.L.获得。

S.D.M. and K.Q.L. jointly supervised this work. The original manuscript draft was written by D.X., U.V.O., S.D.M., and K.Q.L. The manuscript was reviewed and edited by U.V.O., D.X., D.B., S.E., M.M.D., T.N., J.P., N.G.C., I.C.L., S.D.M., and K.Q.L.Corresponding authorsCorrespondence to.

S、 D.M.和K.Q.L.共同监督了这项工作。原稿草稿由D.X.，U.V.O.，S.D.M。和K.Q.L.撰写。原稿由U.V.O.，D.X.，D.B.，S.E.，M.M.D.，T.N.，J.P.，N.G.C.，I.C.L.，S.D.M。和K.Q.L.审查和编辑。通讯作者。

Stephen D. Miller or Kurt Q. Lu.Ethics declarations

Stephen D.Miller或Kurt Q.Lu。道德宣言

Competing interests

相互竞争的利益

S.D.M. is a co-founder of, member of the Scientific Advisory Board, grantee of, and holds stock options in COUR Pharmaceutical Development Company and on COUR Pharma, Inc., which holds the patent for the PLG nanoparticle technology. J.P. is an employee of COUR Pharmaceutical, Inc. The remaining authors declare no conflicts..

S、 D.M.是COUR Pharmaceutical Development Company和on COUR Pharma，Inc.的联合创始人、科学顾问委员会成员、受让人，并持有其股票期权，后者持有PLG纳米颗粒技术的专利。J、 P.是COUR Pharmaceutical，Inc.的员工。其余作者声明没有冲突。。

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Reprints and permissionsAbout this articleCite this articleOnay, U.V., Xu, D., Biyashev, D. et al. Attenuation of skin injury by a MARCO targeting PLGA nanoparticle.

转载和许可本文引用本文Ay，U.V.，Xu，D.，Biyashev，D。等人。通过MARCO靶向PLGA纳米颗粒减轻皮肤损伤。

npj Regen Med 9, 37 (2024). https://doi.org/10.1038/s41536-024-00381-zDownload citationReceived: 12 December 2023Accepted: 19 November 2024Published: 06 December 2024DOI: https://doi.org/10.1038/s41536-024-00381-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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