Serotonin Modulation of Macrophage Polarization: Inflammation and Beyond

Abstract

Macrophages display a ample plethora of effector functions whose acquisition is promoted by the surrounding cytokine and cellular environment. Depending on the stimulus, macrophages become specialized ("polarized") for either pathogen elimination, tissue repair and wound healing or immunosuppression. This "polarization" versatility allows macrophages to critically contribute to tissue homeostasis, as they promote initiation and resolution of inflammatory responses. As a consequence, deregulation of the tissue macrophage polarization balance is an etiological agent of chronic inflammation, autoimmune diseases, cancer and even obesity and insulin resistance. In the present review we describe current concepts on the molecular basis and the patho-physiological implications of macrophage polarization, and describe its modulation by serotonin (5-HT), a neurotransmitter that regulates inflammation and tissue repair via a large set of receptors (5-HTR1-7). 5-HT modulates the phenotypic and functional polarization of macrophages, and contributes to the maintenance of an anti-inflammatory state mainly via 5-HTR2B and 5-HTR7, whose activation has a great impact on macrophage gene expression profile. The identification of 5-HTR2B and 5-HTR7 as functionally-relevant polarization markers suggests their therapeutic value in inflammatory pathologies as well as their potential involvement in linking the immune and nervous systems.

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…Clozapine has been shown to inhibit cellular production of IFN‐γ in human PBMCs through binding of 5HT receptor . 5‐HT can modulate Mac activation by inhibiting LPS‐induced release of TNF‐α and IL‐12, while stimulating IL‐10 release . Further, 5‐HT was found to promote maintenance of rMacs through induction of gene expression associated with resolving activation and inhibition of genes associated with inflammatory activation .…”

Addressing the tuberculosis–depression syndemic to end the tuberculosis epidemic

“…23,34 5-HT affects macrophage polarization (M1 vs. M2 activation states) via 5-HT 2B and 5-HT 7 receptors to induce anti-inflammatory processes. 35 In opposition, pro-inflammatory cytokines activate the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), 30 which divert tryptophan (Trp) to the production of kynurenine (Kyn) instead of 5-HT. As dietary Trp-depletion paradigms have been shown to cause depression relapse, presumably due to decreased 5-HT levels, 36 it was initially postulated that IDO activation may be depressogenic because it reduces 5-HT production in favor of Kyn.…”

Fluoxetine protects against methamphetamine-induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats

“…An etiological agent of chronic inflammation is deregulation of the tissue macrophage polarization balance (9). The modulation of the phenotypic and functional polarization of macrophages is by 5-HT, which regulates the inflammation and the tissue restoration via a large set of receptors (5-HTR1-7) and/or a transporter (9). Lung macrophages express the serotonin transporter (SERT) and 5-HT receptors 2a, and 2b (10).…”