Resolution of Cutaneous Leishmaniasis and Persistence ofLeishmania majorin the Absence of Arginase 1

Abstract

Arginase (Arg) 1 is expressed by hematopoietic (e.g., macrophages) and nonhematopoietic cells (e.g., endothelial cells) and converts L-arginine into ornithine and urea. The enzyme is implicated in tissue repair but also antagonizes the production of NO by type 2 NO synthase in myeloid cells and thereby impedes the control of intracellular parasites such as Leishmania major. In this study, we tested whether Arg1 is required for spontaneous healing of acute cutaneous leishmaniasis in C57BL/6 mice and for lifelong parasite persistence in draining lymph nodes (dLNs) of healed mice. In vitro, bone marrow-derived macrophages and lymphoid endothelial cells readily expressed Arg1 in response to IL-4 and/or IL-13, whereas skin or dLN fibroblasts failed to do so, even during hypoxia. In vivo, Arg1 was found in skin lesions and, to a much lower extent, also in dLNs of acutely infected C57BL/6 mice but became undetectable at both sites after healing. Deletion of Arg1 in hematopoietic and endothelial cells using Tie2Cre +/2 Arg1 fl/fl C57BL/6 mice abolished the expression of Arg1 in skin lesions and dLNs but did not affect development and resolution of skin lesions, parasite burden, NO production, or host cell tropism of L. major during the acute or persistent phase of infection. Similar to wild-type controls, parasites persisting in Arg1-deficient mice favored NO synthase 22negative areas and mainly resided in myeloid cells and fibroblasts. We conclude that Arg1 expression by hematopoietic and endothelial cells is completely dispensable for clinical resolution of cutaneous leishmaniasis and for long-term persistence of L.

Arginase promotes immune evasion of Echinococcus granulosus in mice

“…For example, during murine Toxoplasma gondii infection, ARG-1 in macrophages thwarted effective immunity, impaired parasite control, and elimination of ARG-1 favored host survival [24]. On the contrary, in infections with the Trichuris muris or Leishmania major, mice lacking ARG-1 or ARG-2 showed unaltered cytokine responses, parasite burden and NO production [11,25]. Here, our data showed elevated expression (protein and mRNA levels) and activity of ARG-1 in peritoneal cells from mice with E. granulosus infection.…”

“…In addition to these immunoregulatory effects, ARG-1 expressed by myeloid cells has been involved in promoting tissue repair and wound healing because the l-ornithine is a precursor of proline and polyamines [9,10]. However, in cutaneous leishmaniasis and some tumor models with high arginine-succinate synthetase (ASS1) activity which could produce l-arginine from citrulline, arginase seems to be dispensable for the long-term persistence to pathogens [11,12]. Here, we asked whether arginase was produced and whether its immunosuppression effect was present in Echinococcus granulosus-infected mice, although other immune evasion mechanisms have been found in previous studies [13,14].…”

The outcome of arginase activity inhibition in BALB/c mice hosting Leishmania tropica

“…The level of ARG activity was determined by measuring urea, the enzymatic product, after metabolization of arginine. Since, the highest level of ARG was previously reported in the infected site, 17,20…”

Immunometabolism of Leishmania granulomas

“…The upregulation of myeloid Arg1 may also deplete arginine levels in tissues and inhibit proliferation of hostprotective T cells and other immune cell functions. 44 Many studies have investigated whether enhanced expression of Arg1 in Leishmania-infected M2-polarized macrophages promotes parasite growth beyond antagonizing NO production. In support of such a role, parasites preferentially populate Arg1 + monocytes and macrophages in lesions, and Arg1 expression correlates with increased lesion development in susceptible BALB/c mice.…”