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

Abstract

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 nitric oxide synthase (iNOS or Nos2) dynamic in monocytes/macrophages, which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in macrophages develop increased CHS characterized by elevated ear thickening, monocytes/macrophage-dominated dermal inflammation, and increased iNOS and IL-6 expression compared to control mice. Treatment of Arg1flox/flox; LysMCre+/− mice with a selective NOS inhibitor or knockout of iNOS significantly ameliorated CHS. Our findings suggest a critical role for Arg1 in monocytes/macrophages in suppressing CHS through dampening Nos2 expression. These results may support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.

Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity

“…Although the Ag-specific T cells in ACD are clearly pathogenic, it was previously believed that innate immune cells play a secondary, auxiliary role in mediating tissue damage in the elicitation phase of ACD. However, recent studies have shown that innate immune cells are in fact critical moderators of the efferent phase of ACD (Natsuaki et al, 2014;Suwanpradid et al, 2017b;Tuckermann et al, 2007). These novel mechanisms are illustrated in Figure 1.…”

“…Allergens were found to increase Nos2 expression in macrophages (along with IL-6 and additional proinflammatory cytokines) while also increasing Arg1 (Honda et al, 2013;Kim et al, 2009;Suwanpradid et al, 2017b;Tamoutounour et al, 2013). Specific Arg1 deletion in lysozyme M-expressing cells (including macrophages) aggravated CHS in an in vivo mouse model by increasing iNOS expression, a change that could be mitigated by pharmacologically inhibiting NOS.…”

“…Various cellular signals can cause bona fide macrophages and inflammatory Ly6c hi CCR2 þ monocytes to differentiate into classically activated (M1) or alternatively activated (M2) macrophages Jetten et al, 2014;Sica and Mantovani, 2012;Suwanpradid et al, 2017b;Tamoutounour et al, 2013). M1 macrophages are stimulated by toll-like receptor ligands and IFN-g, causing release of IL-6, IL-12, IL-23, IL-1b, and TNF-a inflammatory cytokines (Colin et al, 2014;Sica and Mantovani, 2012).…”

Overview of RAW264.7 for osteoclastogensis study: Phenotype and stimuli

“…Therefore, combined with previous excellent and novel studies in these fields, 4,32 in our experiences, it might be a reason for different RAW-OC induction efficacies among various study groups. 32 Interestingly, however, as an iNOS inhibitory genes, the Arg1 also highly expressed in another polarized macrophage stage: anti-inflammatory (M2) phenotype, 49,50 and its expression in RAW264.7 has be showed significantly higher in the passage of No. 32 Collin-Osdoby et al 4 32 However, comparing to RAW264.7, the bone marrow macrophage-M0 (BMM-Mφ) has been reported markedly express CD169.…”

“…48 Similarly, genes in subpanel-2 and subpanel-3 also associated with macrophage activation including: CD86, HIF-1α, CD11a, CD18, CD206, CD200R, Glut1 (Glucose transporter 1) and Ly6c and TfR2, Arg1 and SCARA-5b (scavenger receptor class A member 5) respectively. 32 Interestingly, however, as an iNOS inhibitory genes, the Arg1 also highly expressed in another polarized macrophage stage: anti-inflammatory (M2) phenotype, 49,50 and its expression in RAW264.7 has be showed significantly higher in the passage of No. 15.…”