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Page 2 of 10 Yang et al. Plast Aesthet Res 2020;7:34 I http://dx.doi.org/10.20517/2347-9264.2020.24

Keywords: Keloids, psychological stress, adrenergic receptors, dysregulated immune system

INTRODUCTION
Keloids give rise to both cosmetic concerns and functional disabilities as a result of fibroproliferative disorder
and excessive collagen deposition after abnormal wound healing. Furthermore, subjective symptoms
derived from this disease such as pain and pruritus could dramatically affect patients’ quality of life by
causing significant psychological stress. Previous studies have revealed that the genetic background, wound
trauma, foreign body reaction, mechanical stretch, and immune dysfunction are critical risk factors for
keloid development, but the exact mechanism of keloid formation could be more complicated than what
has been found and other risk factors are also likely to be involved, posing challenges to clinical treatment.

[1]
Described as “the non-specific response of the body” , psychological stress has a complicated and
profound influence on the functional state of affected human bodies by secreting various stress hormones.
These primarily include glucocorticoids through the activation of the hypothalamic-pituitary-adrenal
[2]
axis and catecholamines through the sympathetic nervous system . Glucocorticoids can significantly
affect cell metabolism and immune functions in the long term, while the effects of catecholamines
[norepinephrine (NE), epinephrine (E)] are mediated via binding to α-adrenergic receptors (α-AR) or
β-adrenergic receptors (β-ARs) facilitating the human body to react to all kinds of stressors. However, if
the stressful situation becomes overwhelming, the combined action of stress stimulators remains persistent
the physiologically maintained balance maybe disrupted leading to enhancement of pathophysiological
processes for multiple diseases.

Psychological stress has been indicated for contributing to cancer development for decades. For example,
[3]
in patients with lung cancers, stress has become an established predictor of mortality . Stress hormones
(NE, E) can also promote resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor
receptor (EGFR) in non-small cell lung cancer (NSCLC) and increase tumor-derived interleukin-6 (IL-6)
[4]
[5]
overexpression in ovarian cancer cells . Featured with uncontrollable proliferation, invasiveness, and
[6]
glycolysis-dominant metabolic pattern , keloids are regarded as benign skin tumors and the accumulating
literature evidence suggests that certain pathogenic signaling pathways might be shared between keloids
and tumors. As an example, the elevation of IL-6 level, which was determined as a promoting agent in
[7]
NSCLC resistance and its poor prognosis, has also been identified to contribute to keloid formation .
Therefore, it would be reasonable to investigate whether psychological stress influences keloid pathogenesis
and explore the potential of stress hormones (NE, E) as therapeutic targets.

The psychological and mental impacts of pathological scars have been studied in clinical settings and been
reported in an investigation among a black African population. Of this, 48.9% of keloid patients thought
[8]
[9]
they were stigmatized and 35.8% complained about their limited social interactions . Furtado et al. from
Brazil have reported psychological stress as a risk factor for postoperative keloid recurrence in a clinical
study and proposed a novel psycho-neuro-immune-endocrine etiology where they pictured a macroscope
[10]
of the “brain-skin connection” in keloid pathogenesis without mentioning detailed pathways . For quite a
long time, the potential association between stress hormones and keloid pathogenesis has been neglected
according to Pubmed and Embase database searched with key words: keloid AND stress, keloid AND
psychological stress, keloid AND mood disorders. By analyzing the published evidence with regards to
bio-active molecules in keloid tissues and the effects of stress hormones (NE, E) on skin fibroblasts and
immune cells (macrophages) in vitro and immune cytokine profiles both in vitro and in vivo, we outline in
this manuscript three possible signaling pathways that might explain these phenomena.