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Melatonin modulates L-arginine metabolism in tumor-associated macrophages by targeting arginase 1 in lymphoma

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Abstract

L-Arginine metabolism plays a crucial role in determining the M1/M2 polarization of macrophages. The M1 macrophages express inducible nitric oxide synthase (iNOS), while the M2 macrophages express arginase 1 and metabolize arginine into nitric oxide and urea, respectively. The tumor microenvironment promotes M2 macrophage polarization and consequently switches the metabolic fate of arginine from nitric oxide towards urea production. Importantly, infiltration of M2 macrophages or tumor-associated macrophages (TAMs) has been correlated with poor prognosis of various cancer types. Melatonin is well reported to have antitumor and immunomodulatory properties. However, whether and how it impacts the polarization of TAMs has not been elucidated. Considering the crucial role of arginine metabolism in macrophage polarization, we were interested to know the fate of L-arginine in TAMs and whether it can be reinstated by melatonin or not. We used a murine model of Dalton’s lymphoma and established an in vitro model of TAMs. For TAMs, we used the ascitic fluid of tumor-bearing hosts to activate the macrophages in the presence and absence of lipopolysaccharide (LPS). In these groups, L-arginine metabolism was evaluated, and then the effect of melatonin was assessed in these groups, wherein the metabolic fate of arginine as well as the expression of iNOS and arginase 1 were checked. Furthermore, in the in vivo system of the tumor-bearing host, the effect of melatonin was assessed. The in vitro model of TAMs showed a Th2 cytokine profile, reduced phagocytic activity, and increased wound healing ability. Upon investigating arginine metabolism, we observed high urea levels with increased activity and expression of arginase 1 in TAMs. Furthermore, we observed reduced levels of LPS-induced nitric oxide in TAMs; however, their iNOS expression was comparable. With melatonin treatment, urea level decreased significantly, while the reduction in nitric oxide level was not as significant as observed in its absence in TAMs. Also, melatonin significantly reduced arginase activity and expression at the transcriptional and translational levels, while iNOS expression was affected only at the translational level. This effect was further investigated in the in vivo system, wherein melatonin treatment reversed the metabolic fate of arginine, from urea towards nitric oxide, within the tumor microenvironment. This effect was further correlated with pro-apoptotic tumor cell death in the in vivo system. Our results reinforced the immunomodulatory role of melatonin and offered a strong prospect for activating the anti-tumor immune response in cancer conditions.

Graphical abstract

L-arginine metabolism in tumor-associated macrophages (TAMs) within tumor microenvironment and its modulation by melatonin

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DL:

Dalton’s lymphoma

DL-TF:

Dalton’s lymphoma tumor milieu factors

IFNY:

Interferon gamma

IL:

Interleukins

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

MCM:

Macrophage conditioned medium

NO:

Nitric oxide

TAMs:

Tumor-associated macrophages

TGF-β:

Tumor growth factor beta

TNF-α:

Tumor necrosis factor alpha

VC:

Vehicle control

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Acknowledgements

We are grateful to the central instrumentation facility (CIF), Department of Zoology, University of Delhi. Also, the authors are thankful to Prof. Namita Agrawal from the Department of Zoology, University of Delhi, for providing the fluorescence microscope facility.

Funding

This work was supported by research grants to Prof. Anju Shrivastava from the University of Delhi (R&D research grant), DST-PURSE, and a Faculty Research Programme Grant – IoE (Institute of Eminence). The authors received a research fellowship in the form of SRF from CSIR (Council of Scientific and Industrial Research), New Delhi (Anupma Kumari), ICMR (Indian Council of Medical Research), New Delhi (Saima Syeda), and UGC (University Grants Commission), New Delhi (Kavita Rawat and Rani Kumari).

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  1. Department of Zoology, University of Delhi, Delhi, 110007, India

    Anupma Kumari, Saima Syeda, Kavita Rawat, Rani Kumari & Anju Shrivastava

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  1. Anupma Kumari
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AK and AS conceptualized the research. AK performed the experiments and analyzed the results. All the authors did the formal analysis. AK and SS wrote the main manuscript text. All the authors reviewed and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Anju Shrivastava.

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The study was performed in accordance with the guidance for the care and use of laboratory animals with the approval of the University of Delhi and the Committee for the Purpose of Control and Suppression of Experiments on Animals (CPCSEA), India (approval number: DU/ZOOL/IAEC-R/2013/38).

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Kumari, A., Syeda, S., Rawat, K. et al. Melatonin modulates L-arginine metabolism in tumor-associated macrophages by targeting arginase 1 in lymphoma. Naunyn-Schmiedeberg's Arch Pharmacol 397, 1163–1179 (2024). https://doi.org/10.1007/s00210-023-02676-2

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