Propranolol Promotes Monocyte-to-Macrophage Differentiation and Enhances Macrophage Anti-Inflammatory Activities

Propranolol and Monocyte-to-Macrophage Differentiation

Adrenergic pathways represent the main channel of communication between the nervous system and the immune system [1]. This cross-talk is required to restore homeostasis after tissue inflammation. During inflammation, blood monocytes migrate within tissue and differentiate into macrophages. They are phagocytic innate immune cells that contribute to maintain homeostasis through the clearance of apoptotic cells and the production of growth factors [2]. These cells are able to remove invading pathogens through their phagocytic and antigen-presenting activities and play a central role in the regulation of tissue remodelling/healing, cell proliferation and angiogenesis [3,4].

Macrophages are activated by local cytokines and mediators and polarize to M1 or M2 macrophages. M1 activity inhibits cell proliferation and causes tissue damage, while M2 activity promotes cell proliferation and tissue repair. In general, M1 macrophages are considered proinflammatory cells, whereas M2 macrophages are anti-inflammatory [5].

M1/M2 macrophages are involved in the pathogenic mechanisms of several diseases. It has been demonstrated that macrophage polarization influences the outcome of infections, chronic inflammatory diseases and tumors, and developing strategies to control this process may have a beneficial impact on the prevention and treatment of different pathologies.

Both monocytes and macrophages express β-adrenergic receptors (β-ARs). Thus, the regulation of monocyte/macrophage functions can be achieved by modulating β-AR activity. The main β-ARs expressed in innate immune cells are of the β1 and β2 subtypes, which are known to influence cell inflammatory response. The functional consequences of β-AR signaling on monocyte/macrophage activation are often anti-inflammatory and immunosuppressive [6,7], although under certain conditions, they can result in pro-inflammatory effects [8].

β-ARs are G-protein-coupled receptors with a role in the regulation of peripheral vascular resistance, heart function, metabolism and airway tone. These receptors are the target of catecholamines and β-blockers, a class of drugs that inhibits the effects of catecholamines such as noradrenaline and adrenaline. Propranolol, a non-selective β-AR antagonist, is the prototype of β-blockers with a great affinity for β1- and β2-ARs [9]. It has been widely evaluated in preclinical studies and is used to treat a variety of clinical conditions, such as capillary hemangioma, supraventricular arrhythmias, migraine and arterial hypertension.

In a rat model of cerebral ischemia, treatment with propranolol, attenuated hyperglycemia, inflammation and brain injury, and improved the clinical outcome of experimental autoimmune encephalomyelitis (EAE) [10]. The protective effect of propranolol administration has been associated with the increased number of anti-inflammatory CD163- and IL-10-expressing microglia and the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase(HO)-1 axis, which regulates multiple cytoprotective responses [11].

In a recent study published in the International Journal of Molecular Sciences we used molecular biology, flow cytometry and immunoenzymatic analyses to investigate whether the β-AR-blocking drug propranolol was able to modulate in vitro human monocyte-to-macrophage differentiation and to further influence the activation states of polarized macrophages. Human monocytes were isolated from peripheral blood and cultured for 6 days with M-CSF in the presence or absence of propranolol and then activated toward a M1 pro-inflammatory state, or a M2 anti-inflammatory/regulatory state.

A chronic exposure of monocytes to propranolol during their differentiation into macrophages in vitro promoted the increase of the M1 markers CD16 and of the M2 markers CD206, CD163 and peroxisome proliferator-activated receptor g (PPAR-g) expression. It also increased endocytosis and the release of the anti-inflammatory cytokine IL-10, whereas it reduced physiological reactive oxygen species. Exposure to pro-inflammatory condition of propranolol- differentiated macrophages resulted in an anti-inflammatory promoting effects.

Figure 1. Chronic exposure of human monocytes to propranolol during their differentiation into macrophages shifts these macrophages towards an M2-like phenotype, enhancing their anti-inflammatory clearance capabilities. This M2-promoting effect of propranolol is linked to the simultaneous activation of NRF2- and PPAR-γ-dependent antioxidant and anti-inflammatory genes. This mechanism may help explain the improved survival rates observed in patients with cancer, as well as those with a history of myocardial infarction and atherosclerosis, who are undergoing β-blocker-based therapies.

At the molecular level, propranolol upregulated the expression of oxidative stress regulators such as the transcription factor nuclear factor E2-related factor 2 (NRF2), heme oxygenase-1 and NAD(P)H Quinone Dehydrogenase 1 (NQO1). Collectively, these results suggest that β-ARs are involved in the induction of regulatory macrophages and that the binding of propranolol to β-ARs expressed by monocyte/macrophage populations can promote the differentiation of human monocytes towards M2-like macrophages by activating the expression of NRF2- and PPAR-γ-dependent antioxidant and anti-inflammatory genes simultaneously.

In conclusion, growing evidence suggests that there is a cross-talk between the sympathetic nervous system and the immune system. Therefore, it is not surprising that some inflammatory diseases have been associated with β-AR dysregulation. For example, Crohn’s disease, systemic lupus erythematosus, and rheumatoid arthritis (12-14) are associated with β-AR downregulation on peripheral blood mononuclear cells.

Given that regulatory macrophages can render the host prone to infection or, conversely, attenuate vigorous but damaging inflammation, modulation of the adrenergic system by β-blockers such as propranolol may be an important therapeutic avenue to protect the host from exaggerated inflammatory responses. Further studies will be needed to better understand the network of molecules that orchestrate the regulation of macrophage biology by β-blockers and to determine whether a therapy can be based on these findings.

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Author Affiliations:

Sonia Maccari, Center for Gender Medicine, Italian National Institute of Health, 00161 Rome, Italy; sonia.maccari@iss.it

Elisabetta Profumo, Department of Cardiovascular and Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy; elisabetta.profumo@iss.it

Luciano Saso, Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, 00185 Rome, Italy; luciano.saso@uniroma1.it

Giuseppe Marano, Center for Gender Medicine, Italian National Institute of Health, 00161 Rome, Italy; giuseppe.marano@iss.it

Brigitta Buttari, Department of Cardiovascular and Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy; brigitta.buttari@iss.it

Source: Maccari S, Profumo E, Saso L, Marano G, Buttari B. Propranolol Promotes Monocyte-to-Macrophage Differentiation and Enhances Macrophage Anti-Inflammatory and Antioxidant Activities by NRF2 Activation. Int J Mol Sci. 2024 Mar 26;25(7):3683. doi: 10.3390/ijms25073683.

Read More: International Journal of Molecular Sciences

Cover Image Credit (right): Macrophage polarization. Monocyte-derived-macrophages can be polarized ex vivo and in vivo into pro- or anti-inflammatory macrophages in response to different stimuli. Pro-inflammatory macrophages are involved in the anti-microbial and anti-tumor response and are implicated in the evolution of several pathologies such as atherosclerosis or type 2 diabetes. Anti-inflammatory macrophages exhibit an immunosuppressive activity, are involved in tissue repair, and promote angiogenesis. They are also involved in the evolution of various pathologies including fibrosis and tumor progression. From: The generation, activation, and polarization of monocyte-derived macrophages in human malignancies, Front. Immunol., 18 April 2023 Sec. Cancer Immunity and Immunotherapy Volume 14 – 2023 | https://doi.org/10.3389/fimmu.2023.1178337

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