Abstract
Metabolism of the amino acid L-arginine is implicated in many physiological and pathophysiological processes including autoimmune conditions such as type 1 diabetes (T1D). Alternate arginine metabolism through the citrulline-nitric oxide (NO) or the ornithine pathways can lead to proinflammatory or immune regulatory effects, respectively. In this report, we blocked the arginine-ornithine metabolic pathway by inhibiting the enzyme arginase-1 with Nω-hydroxy-nor-arginine (nor-NOHA) to make arginine more available to the alternate citrulline pathway for augmented NO production and increased incidence of autoimmune T1D in female non-obese diabetic (NOD) mice. Unexpectedly, mice receiving nor-NOHA did not develop diabetes although increased NO production is proinflammatory and expected to increase diabetes incidence. These results warrant further studies of the mechanism of action of nor-NOHA, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.
Highlights
Curr Res Diabetes Obes J 5(3): CRDOJ.MS.ID.555661 (2018)Current Research in Diabetes & Obesity JournalThe role of L-arginine metabolism in autoimmune diseases has recently become of interest
We investigated arginine metabolism and the spontaneous incidence of autoimmune diabetes as a function of age in female non-obese diabetic (NOD) mice, and evaluated the effect of nor-NOHA treatment on diabetes incidence
At week 26, ornithine was reduced by ~30% and citrulline was elevated by ~20% in diabetic mice (D-NOD) compared to non-diabetic controls (ND-NOD) (Figure 2A)
Summary
Curr Res Diabetes Obes J 5(3): CRDOJ.MS.ID.555661 (2018)Current Research in Diabetes & Obesity JournalThe role of L-arginine metabolism in autoimmune diseases has recently become of interest. Metabolic products of two alternate arginine metabolism pathways (Figure 1) are implicated in both proinflammatory/autoimmune and immune regulatory/tolerogenic immune responses. The alternate ornithine pathway of arginine metabolism favors polarization towards immunoregulatory function in immune cells such as regulatory T cells (Tregs) and M2 macrophages, which are essential during resolution of inflammation, tissue healing, and immune tolerance induction/maintenance. When the enzyme arginase-1 is overexpressed, arginine is metabolized to urea, ornithine, and downstream polyamines that are crucial building blocks during cell proliferation and maintenance of tissue homeostasis. We hypothesized that administration of an arginase-1 inhibitor should block the urea-ornithine pathway making arginine more available for the alternate citrullineNO pathway for increased production of NO and associated tissue inflammation and, increased incidence of autoimmune diabetes (Figure 1)
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