Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity

The innate immune components that modulate allergic contact hypersensitivity (CHS) responses are poorly defined. Using human skin from contact dermatitis patients and a mouse model of CHS, we find that hapten allergens disrupt the Arginase1 (Arg1) and inducible NO synthase (iNOS) dynamic in monocytes/macrophages (mono/M Phi), which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in M Phi develop increased CHS characterized by elevated ear thickening, mono/M Phi 2 dominated dermal inflammation, and increased iNOS and IL-6 expression compared with control mice. Treatment of Arg1(flox/flox); LysMCre(+/-) mice with a selective NOS inhibitor or knockout of Nos2, encoding iNOS, significantly ameliorates CHS. Our findings suggest a critical role for Arg1 in mono/M Phi in suppressing CHS through dampening Nos2 expression. These results support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.