Polyamine import and accumulation causes immunomodulation in macrophages engulfing apoptotic cells

• Published in: Cell reports (Cambridge) 2022-01, Vol.38 (2), p.110222-110222, Article 110222
• Main Authors: McCubbrey, Alexandra L., McManus, Shannon A., McClendon, Jazalle D., Thomas, Stacey M., Chatwin, Hope B., Reisz, Julie A., D’Alessandro, Angelo, Mould, Kara J., Bratton, Donna L., Henson, Peter M., Janssen, William J.
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - physiology; arginine; Cytophagocytosis - physiology; efferocytosis; Female; Healthy Volunteers; Humans; Immunomodulation; Inflammation - metabolism; macrophage; Macrophages - immunology; Macrophages - metabolism; Male; metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; polyamines; Polyamines - metabolism; Signal Transduction; Spermidine - metabolism; Spermine - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110222

Phagocytosis of apoptotic cells, termed efferocytosis, is critical for tissue homeostasis and drives anti-inflammatory programming in engulfing macrophages. Here, we assess metabolites in naive and inflammatory macrophages following engulfment of multiple cellular and non-cellular targets. Efferocytosis leads to increases in the arginine-derived polyamines, spermidine and spermine, in vitro and in vivo. Surprisingly, polyamine accumulation after efferocytosis does not arise from retention of apoptotic cell metabolites or de novo synthesis but from enhanced polyamine import that is dependent on Rac1, actin, and PI3 kinase. Blocking polyamine import prevents efferocytosis from suppressing macrophage interleukin (IL)-1β or IL-6. This identifies efferocytosis as a trigger for polyamine import and accumulation, and imported polyamines as mediators of efferocytosis-induced immune reprogramming. [Display omitted] •Efferocytosis triggers macrophages to accumulate polyamines spermidine and spermine•Polyamine accumulation is mediated by Rac1-dependent endocytic import•Inhibition of polyamine import blunts immunomodulation in response to efferocytosis McCubbrey et al. show that efferocytosis elicits accumulation of intracellular polyamines, spermidine and spermine, in engulfing macrophages. Efferocytosis does not increase polyamine synthesis but triggers endocytic import of polyamines. Blocking endocytic import prevents polyamine accumulation after efferocytosis and reduces the ability of efferocytosis to suppress IL-1β and IL-6.