Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Abstract

Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via L-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes L-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.

Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients

“…Among persons with HIV infection, granuloma formation is impaired. Unlike immunocompetent persons, in whom granulomas display a finely organized architecture with spatially modulated gradients of T-cell and macrophage phenotypes [10][11][12], patients with tuberculosis with advanced HIV infection develop disorganized granulomas that are poorly contained collections of polymorphonuclear cells and eosinophils with a paucity of mononuclear, epithelioid, or giant cells [13][14][15][16][17]. Poorly contained lesions in animal tissues are not hypoxic, and this may also be the case in HIV-infected patients with tuberculosis [8,9,18,19].…”

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

“…To mechanistically address if arginase-1 expression in macrophages mediates the exacerbated disease seen in helminth/Mtb-coinfected mice, we then generated BM chimeric mice (BMC mice). The Tie2-Cre deleter is active in all hematopoietic cells, but as arginase-1 is predominantly expressed in macrophages in TB and schistosomiasis (18,19), use of Tie2-Cre Arg1 fl/fl BM cells for reconstitution of BMC will delete arginase-1 in macrophages (18)(19)(20)(21)(22). In addition, as only BM myeloid cells lacking arginase-1 were transferred, any effects of host-derived endothelial arginase-1 are avoided.…”

“…The fact that S. mansoni/Mtb-coinfected BMC mice that lack arginase-1-expressing macrophages exhibit decreased lung inflammation and increased formation of protective B cell follicles provides direct evidence that helminth-induced arginase-1 expression in myeloid cells mediates disease exacerbation in coinfected hosts. Interestingly, in a dermal Mtb-infection model resulting in hypoxic lung granulomas, absence of arginase-1 in macrophages resulted in exacerbated inflammation in iNOS-deficient mice (21). It is possible that arginase-1 expression in macrophages can function to either limit or exacerbate inflammation, depending upon the availability or absence of iNOS, and this needs to be carefully examined in the future.…”

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

“…This process can be interrupted by arginase activity, which hydrolyzes L-arginine to L-ornithine and urea, thereby competing with iNOS for bioavailable L-arginine. Similar to iNOS, type 1 arginase (Arg1) is induced in human MFs within TB granulomas and in the lungs of mice infected with M. bovis BCG (16)(17)(18)(19), suggesting substrate competition for L-arginine in vivo. Indeed, mice lacking Arg1 in MFs make more NO and clear M. tuberculosis faster than do control mice (20).…”