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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/MΦ), which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in MΦ develop increased CHS characterized by elevated ear thickening, mono/MΦ−dominated dermal inflammation, and increased iNOS and IL-6 expression compared with control mice. Treatment of Arg1flox/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/MΦ in suppressing CHS through dampening Nos2 expression. These results support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.

Background Respiratory exposure to crystalline silica in man is associated with autoimmunity that includes a prominent humoral component. We hypothesize that autoimmune B cell recruitment and regulation are altered in silica-exposed lungs in genetically susceptible individuals. Methods Wildtype and autoAb transgenic (Tg+) mice of B6 and lupus-prone NZB, MRL, and BXSB backgrounds were exposed to silica dust or vehicle by oropharyngeal aspiration. After 1–3 months, lung pathology and lymphocytic infiltrates were scored. Lupus and vasculitis autoAb levels were measured in bronchoalveolar lavage fluid (BALF), serum, and supernatants from cultured lung and spleen cells. Results All silica-exposed strains showed extensive lung pathology and focal B and T cell infiltrates consistent with ectopic lymphoid structures (ELS). In wildtype mice, % lung area containing ELS after silica exposure varied by strain (BXSB>MRL>B6>NZB, p=0.03). Significant increases in autoAb production with silica exposure were observed in BALF, lung cell supernatants, and serum, and varied by genetic background. Among Tg+ mice, Tg+ Ig levels in BALF were higher in silica- vs vehicle-exposed mice in B6 and BXSB strains (p Conclusions Respiratory exposure to silica leads to pulmonary B and T cell accumulation with ELS formation and enhanced autoAb production. This occurs in a strain-dependent manner, highlighting the impact of genetic influences on silica-induced autoimmunity. Evidence of local autoAb secretion implicates dysregulated control of autoreactive B cells at the environment/lung interface, possibly through the intermediary of silica-induced ELS.