Investigating the role of serotonergic receptor subtypes in the modulation of cell-specific immune function

Abstract

Serotonin (5-Hydroxytryptamine) is a phylogenetically conserved biogenic monoamine that can function as a neurotransmitter, hormone, and mitogen across diverse tissues. Beyond the nervous system, serotonergic signalling contributes to immune regulation through its group of seven receptor families, comprising multiple subtypes. Although nearly all immune cells express at least one serotonergic receptor, alongside many immunomodulatory functions being attributed to serotonergic signalling, the full extent of receptor distribution and its functions remains poorly defined. This thesis investigated serotonergic receptor expression and function in
murine immune cells, with the overarching aim of identifying how serotonergic signalling shapes the immune response at the cell-specific level. We first analysed transcriptomic datasets from murine and human immune cell populations, before confirming the expression of specific receptors by RT-PCR in key immune cell populations. These analyses revealed widespread, but
heterogeneous, receptor expression, with partial conservation across species. We next examined the impact of receptor-selective and non-selective agonists on murine immune cells in a primary mixed in vitro splenocyte model, specifically investigating immune population dynamics, activation, and exhaustion, as well as cytokine signalling. The most significant effects
were associated with HTR1a and/or HTR7 stimulation, which induced a reduction in B cells in unstimulated cultures, while CD3-stimulation was shown to reverse this effect. Furthermore, several other responses suggested that serotonergic signalling imposed an immunosuppressive action, characterised by reductions in immune cell numbers, decreased activation, increased exhaustion, and reduced cytokine signalling. To assess the translatability and relevance of these in vitro findings, we pharmacologically modulated serotonergic signalling in an LPS (lipopolysaccharide)-induced murine model of systemic inflammation with non-selective serotonergic agonists. In contrast to the in vitro observations, in vivo manipulations of serotonergic signalling produced no observable effects across behavioural or immunological parameters, likely highlighting the complexity of serotonergic-mediated regulation within the in vivo immune environment. Collectively, these results demonstrate that serotonergic receptors are broadly expressed in murine and human immune cells, and that selective activation can modulate immune function in vitro. However, the divergence between the in vitro and in vivo findings likely highlights the need to consider serotonergic signalling alongside other immunoregulatory networks. Together, these findings support the conclusion that serotonergic signalling contributes to immune regulation, likely not as the dominant signal, but instead as a context-dependent modulator acting alongside other immunoregulatory pathways.

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Identifiers

ORCID for Jamie Lee Thomas: orcid.org/0000-0002-8447-3504

ORCID for Diego Gomez-Nicola: orcid.org/0000-0002-5316-2682

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