Suppression of Hyperactive Immune Responses Protects against Nitrogen Mustard Injury.
DNA alkylating agents like nitrogen mustard (NM) are easily absorbed through the skin and exposure to such agents manifest not only in direct cellular death but also in triggering inflammation. We show that toxicity resulting from topical mustard exposure is mediated in part by initiating exaggerated host innate immune responses. Using an experimental model of skin exposure to NM we observe activation of inflammatory dermal macrophages that exacerbate local tissue damage in an inducible nitric oxide synthase (iNOS)-dependent manner. Subsequently these activated dermal macrophages reappear in the bone marrow to aid in disruption of hematopoiesis and contribute ultimately to mortality in an experimental mouse model of topical NM exposure. Intervention with a single dose of 25-hydroxyvitamin D3 (25(OH)D) is capable of suppressing macrophage-mediated iNOS production resulting in mitigation of local skin destruction, enhanced tissue repair, protection from marrow depletion, and rescue from severe precipitous wasting. These protective effects are recapitulated experimentally using pharmacological inhibitors of iNOS or by compounds that locally deplete skin macrophages. Taken together, these data highlight a critical unappreciated role of the host innate immune system in exacerbating injury following exposure to NM and support the translation of 25(OH)D in the therapeutic use against these chemical agents.
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Chemical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Liemin
L
Au
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
Jeffrey P
JP
Meisch
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
Lopa M
LM
Das
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA.
Amy M
AM
Binko
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado, USA.
Rebecca S
RS
Boxer
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Amy M
AM
Wen
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA; Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Material Science and Engineering, Case Western Reserve University, Cleveland, Ohio, USA; Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Nicole F
NF
Steinmetz
Department of Dermatology, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address: kurt.lu@case.edu.
Kurt Q
KQ
Lu
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002112:Calcifediol / Q000494:pharmacology*; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D008231:Lymphopenia / Q000188:drug therapy; D008264:Macrophages / Q000502:physiology; D008466:Mechlorethamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors
D008466:Mechlorethamine; D052247:Nitric Oxide Synthase Type II; D002112:Calcifediol