A human and animal model-based approach to investigating the anti-inflammatory profile and potential of the 5-HT2B receptor antagonist AM1030

Abstract

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Side-effects and safety concerns associated with these agents restrict their use, and new, safe treatment options are therefore needed. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor family may contribute to inflammation and pruritus in the skin. The objective of this particular study was to investigate the 5HT2B receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential.MethodsAM1030 was tested in a set of distinct human and rodent in vitro and in vivo models, differing with respect to e.g. T cell involvement, triggering stimulus, main read-outs and route of drug administration. The in vitro systems used were staphylococcal enterotoxin A (SEA)-stimulated human peripheral blood mononuclear cells, lipopolysaccharide (LPS)-stimulated human primary monocytes, LPS-stimulated human THP-1 monocytes and LPS-stimulated mouse primary macrophages. The in vivo systems used were LPS- and SEA-induced cytokine production in the mouse, antigen-induced arthritis in the rat, glucose-6-phosphate isomerase-induced arthritis in the mouse and delayed-type hypersensitivity reaction in the mouse. In addition, different cell populations were analyzed with respect to their expression of the 5-HT2B receptor at the mRNA level.ResultsAM1030 significantly reduced both T cell-dependent and T cell-independent inflammatory responses, in vivo and in vitro. Due to the low or absent expression of the 5-HT2B receptor on T cell populations, the influence of AM1030 in T cell-dependent systems is suggested to be mediated via an indirect effect involving antigen-presenting cell types, such as monocytes and macrophages.ConclusionBased on the wide range of model systems used in this study, differing e.g. with respect to species, T cell involvement, triggering stimuli, route of drug administration and read-outs, our results suggest a broad anti-inflammatory effect of AM1030 and identify the 5-HT2B receptor as a promising future target for anti-inflammatory intervention, e.g. in AD.

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

“…Consistent with these findings, we have shown that 5HTR2A/2B/2C antagonists decreased mRNA expression and levels of proinflammatory cytokine in cholangiocytes from BDL rats and Mdr2 –/– mice compared to control animals. Supporting our findings, AM1030 (an antagonist of 5HTR2B) displays anti‐inflammatory properties against LPS‐induced atopic dermatitis . Consistent with previous findings showing that damaged/proliferating cholangiocytes acquire neuroendocrine phenotypes and secrete a number of neuroendocrine factors (e.g., melatonin, 5HT, sex hormones, secretin, VEGF, and nerve growth factor) that regulate biliary homeostasis during cholestasis, we demonstrate that cholangiocytes (in addition to HSCs) express TPH1 and secrete 5HT, parameters that were increased in both BDL rats and Mdr2 –/– mice and human PSC serum samples (5HT levels).…”

“…Supporting our findings, AM1030 (an antagonist of 5HTR2B) displays anti-inflammatory properties against LPS-induced atopic dermatitis. (40) Consistent with previous findings showing that damaged/proliferating cholangiocytes acquire neuroendocrine phenotypes and secrete a number of neuroendocrine factors (e.g., melatonin, 5HT, sex hormones, secretin, VEGF, and nerve growth factor) (4,7,17,18,20,29) that regulate biliary homeostasis during cholestasis, we demonstrate that cholangiocytes (in addition to HSCs) express TPH1 and secrete 5HT, parameters that were increased in both BDL rats and Mdr2 -/mice and human PSC serum samples (5HT levels). Parallel to our findings in cholangiocytes and HSCs, several studies support the existence of paracrine/autocrine serotonergic networks in both the brain and peripheral organs, (41,42) given that MAO-A and TPH1 are present in the brain as well as lungs, kidneys, thyroid, heart, and liver.…”

5-HT2Bserotonin receptor agonist BW723C86 shapes the macrophage gene profile via AhR and impairs monocyte-to-osteoclast differentiation

“…have been widely used in vivo to support the participation of 5-HT 2B in several animal models of disease 73,74,86,87,[89][90][91][124][125][126] , our results suggests the possibility that AhR might have influenced some of these previous results and might have even contributed to the pathological effects of deregulated 5-HT 2B expression or function. As an example, since AhR mediates IL-10 production and promotes immunological tolerance after macrophage capture of apoptotic cells 127 , AhR might contribute to the anti-inflammatory effect of 5-HT 2B in mouse microglia 71 and human monocytes 72 . On a related note, the assessment of the extent of the transcriptional action of BW723C86 evidenced that the effects of the agonist on the expression of more than 200 genes (including some encoding regulators of osteoclastogenesis) are not prevented by the 5-HT 2B antagonist SB204741 (Figure 1).…”

“…In macrophages, 5-HT 2B prevents mononuclear phagocyte degeneration in amyotrophic lateral sclerosis 70 , and Htr2b -/microglia exhibits a mild inflammatory state 71 , which is in line with the ability of 5-HT 2B antagonist SB204741 to impair the acquisition of human macrophage polarization-specific genes 40 and TGFβ1 expression by mouse Kupffer cells 45 . However, although 5-HT 2B activation modifies inflammatory cytokine production by human monocytes 72 , the functional and transcriptional consequences of 5-HT 2B ligation in human macrophage remains to be determined. Since antiinflammatory M-CSF-dependent macrophages express 5-HT 2B , we have assessed the specific role of 5-HT 2B in macrophage polarization.…”

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies

“…The aminoguanidine derivative and 5-HT 2B receptor antagonist AM1030 significantly diminished the T-cell-dependent and the T-cell-independent inflammatory responses in in vivo mouse and rat models and in an in vitro setting with staphylococcal enterotoxin A-stimulated leukocytes [101]. AM1030 is similar to a previously investigated agent demonstrating anti-inflammatory properties [102], and has been evaluated in a phase I/II study of 36 adults with mild to severe AD (NCT02379910).…”