The role of polyamines in the regulation of macrophage polarization and function

Yvonne L Latour, Alain P Gobert, Keith T Wilson, Yvonne L Latour, Alain P Gobert, Keith T Wilson

Abstract

Naturally occurring polyamines are ubiquitously distributed and play important roles in cell development, amino acid and protein synthesis, oxidative DNA damage, proliferation, and cellular differentiation. Macrophages are essential in the innate immune response, and contribute to tissue remodeling. Naïve macrophages have two major potential fates: polarization to (1) the classical pro-inflammatory M1 defense response to bacterial pathogens and tumor cells, and (2) the alternatively activated M2 response, induced in the presence of parasites and wounding, and also implicated in the development of tumor-associated macrophages. ODC, the rate-limiting enzyme in polyamine synthesis, leads to an increase in putrescine levels, which impairs M1 gene transcription. Additionally, spermidine and spermine can regulate translation of pro-inflammatory mediators in activated macrophages. In this review, we focus on polyamines in macrophage activation patterns in the context of gastrointestinal inflammation and carcinogenesis. We seek to clarify mechanisms of innate immune regulation by polyamine metabolism and potential novel therapeutic targets.

Keywords: Colitis; Gastric cancer; Macrophages; Polarization; Polyamines.

Conflict of interest statement

Conflict of interest. The authors declare that no conflict of interest exists.

Figures

Fig. 1
Fig. 1
Overview of polyamine synthesis and the effect on macrophage polarization. Putrescine is converted to spermidine by spermidine synthase (SRM) and spermidine is converted to spermine by spermine synthase (SMS). Spermine oxidase (SMOX) back-converts spermine to spermidine. Macrophages have two main polarization states; classically activated pro-inflammatory M1 macrophages and alternatively activated, anti-inflammatory and pro-tumoral M2 macrophages. Putrescine inhibits the formation of euchromatin thus downregulating the expression of M1 genes. Spermidine favors M1 polarization while spermine favors M2
Fig. 2
Fig. 2
Regulation of macrophage function by polyamine synthesis. In general, once activated, M1 macrophages metabolize L-arginine by NOS2 to produce NO while M2 macrophages (Mregs, TAMs, MDSCs, M2a) upregulate the ARG1/2-ODC pathway to produce polyamines, however, both retain the ability to change activation states. Putrescine downregulates transcription of M1 genes including Nos2 and spermine inhibits the translation of NOS2, thus hindering an M1 response. Spermine also supports autophagy via ATG5, which inhibits M1 polarization while promoting M2 polarization. In contrast, spermidine upregulates transcription of Nos2 and can both directly and indirectly inhibit tumor growth. TAM survival is mediated by upregulation of ABHD5, which suppresses spermidine by inhibiting translation of spermidine synthase (SRM)

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