Immune-Regulatory and Molecular Effects of Antidepressants on the Inflamed Human Keratinocyte HaCaT Cell Line

Abstract

Allergic contact dermatitis (ACD) is a T cell-mediated type of skin inflammation resulting from contact hypersensitivity (CHS) to antigens. There is strong comorbidity between ACD and major depression. Keratinocytes release immunomodulatory mediators including pro-inflammatory cytokines and chemokines, which modulate skin inflammation and are crucial cell type for the development of CHS. Our previous studies showed that fluoxetine and desipramine were effective in suppressing CHS in different mouse strains. However, the immune and molecular mechanisms underlying this effect remain to be explored. The aim of the current study was to determine the immune and molecular mechanisms of action of antidepressant drugs engaged in the inhibition of CHS response in the stimulated keratinocyte HaCaT cell line. The results show that LPS, TNF-α/IFN-γ, and DNFB stimulate HaCaT cells to produce large amounts of pro-inflammatory factors including IL-1β, IL-6, CCL2, and CXCL8. HaCaT stimulation was associated with increased expression of ICAM-1, a cell adhesion molecule, and decreased expression of E-cadherin. Imipramine, desipramine, and fluoxetine suppress the production of IL-1β, CCL2, as well as the expression of ICAM-1. LPS and TNF-α/IFN-γ activate p-38 kinase, but antidepressants do not regulate this pathway. LPS decreases E-cadherin protein expression and fluoxetine normalizes these effects. In summary, the antidepressant drugs examined in this study attenuate the stimulated secretion of pro-inflammatory cytokines, chemokines, and modulate adhesion molecule expression by the HaCaT cell line. Therefore, antidepressants may have some clinical efficacy in patients with ACD and patients with comorbid depression and contact allergy.

Assessment of Comorbidities Associated With Allergic Contact Dermatitis in the United States: A Retrospective Claims-Based Study

“…Interestingly, a prior study demonstrated the efficacy of antidepressant drugs in suppressing contact hypersensitivity by attenuating the secretion of proinflammatory molecules, including IL-1β, CCL2, and ICAM-1, in a murine model, which might suggest a shared pathophysiologic pathway between ACD and depression. 17 Notably, we also found an association between ACD and comorbidities that involve sleep disturbance, such as insomnia and daytime somnolence. Sleep impacts daily activities, work productivity, mood, and mental health.…”

“…Patients with ACD used psychiatric medications at higher rates than non-ACD patients. Interestingly, a prior study demonstrated the efficacy of antidepressant drugs in suppressing contact hypersensitivity by attenuating the secretion of proinflammatory molecules, including IL-1β, CCL2, and ICAM-1, in a murine model, which might suggest a shared pathophysiologic pathway between ACD and depression 17 …”

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

“…FX is a widely used antidepressant agent that belongs to the SSRI family. 21 It possesses a remarkable safety profile, 42,43 and it was also shown to exert anti-inflammatory, [23][24][25][26] anti-pruritic, 27,28 prowound healing, 30,31 and anti-AD 32 effects. Thus, it is not surprising that it has already been recommended to treat various diseases and pathological conditions outside of its current indication as an antidepressant.…”

“…21 Importantly, besides its 'core' effects on the central nervous system, it has been shown to exert remarkable anti-inflammatory actions in various systems, including the skin. [22][23][24][25][26] Moreover, it has clinically relevant anti-pruritic effects, 27,28 it appears to promote (re)pigmentation of microdissected human hair follicles, 29 it improves wound healing following topical application in diabetic mice 30 as well as in humans with infected wounds, 31 and it was demonstrated to ameliorate AD-like skin lesions in a murine model of AD. 32 Moreover, recent studies demonstrated that, most likely due to direct antiviral and immune regulatory effects, FX administration beneficially influenced the clinical outcome in SARS-CoV-2 infection as well.…”

“…Fluoxetine (FX) is a selective serotonin reuptake inhibitor (SSRI) that has been in clinical use as an antidepressant agent since 1988 21 . Importantly, besides its ‘core’ effects on the central nervous system, it has been shown to exert remarkable anti‐inflammatory actions in various systems, including the skin 22–26 . Moreover, it has clinically relevant anti‐pruritic effects, 27,28 it appears to promote (re)pigmentation of microdissected human hair follicles, 29 it improves wound healing following topical application in diabetic mice 30 as well as in humans with infected wounds, 31 and it was demonstrated to ameliorate AD‐like skin lesions in a murine model of AD 32 .…”