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Yang et al. Plast Aesthet Res 2020;7:34  I  http://dx.doi.org/10.20517/2347-9264.2020.24                                            Page 7 of 10
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               The Foxp3 CD4  regulatory T (Treg) cells represent a critical T cell subset, the dysfunction of which was
                                                      [69]
                                                                                                       +
               implicated in multiple inflammatory diseases . While the normal skin displays a relative lack of CD3  T
                                    +
               cells, the levels of Foxp3  Treg were significantly higher in keloid tissues (range of 25.5%-72.5%) in contrast
               to those in the circulation of keloid patients (4%-10.5%) . Additionally, it was also observed in the same
                                                               [68]
                                                   +
               research that incubating circulating CD3  T cells with keloid macrophages could significantly raise the
               expression of Foxp3, suggesting that these keloid macrophages could promote Treg differentiation by
               upregulating Foxp3 expression.
               Even though no research on the levels of macrophages and depression in patients with skin conditions has
               been reported thus far, other previous studies did show that the activation and polarization of microglia
               (central nervous system-resident macrophages) could modulate the production and secretion of pro-
               inflammatory cytokines, implicating the involvement of macrophages in the etiology of major depressive
                                                                           [70]
               disorder, which was referred as the “macrophage theory of depression” . In light of this, it could be argued
               that an abundance of pro-inflammatory cytokines induced by the altered profile of macrophages inside
               keloids might exist, and further investigations, therefore, need to be performed in keloid patients with
               diagnosed depression.

               The tumor necrosis factor
               TNF produced by monocytes and macrophages during the inflammatory phase has been known to induce
               collagen degranulation and minimize excessive scarring possibly by increasing the MMP1/TIMP3, MMP2/
                           [71]
               TIMP3 ratios .

               Various animal and patient-based clinical studies have demonstrated the associations between the
               concentration of pro-inflammatory cytokines, specifically IL-1β, IL-6, TNF, and depressive symptoms .
                                                                                                       [15]
               They also showed a general normalization (decline) of IL-6 and TNF concentration after antidepressant
               treatment [72,73] .

               CONCLUSION
               As a benign skin tumor outgrowing the original wound boundary or growing spontaneously on the
               normal skin, keloid can bring great pain and inconvenience to patients. Although risk factors such as genes
               and infection have been noticed, the pathologic mechanisms remain unclear, leading to challenges for
               treatment resistance and keloid recurrence, including 9%-50% recurrent rate of the corticosteroid injection,
               45%-100% recurrence rate of the surgical removal and 9.59% relapse rate of the radiotherapy .
                                                                                             [44]
               Psychological stress evoked by traumatic events and depressive conditions has huge impacts on the overall
               health state. Through stress hormones (NE, E, glucocorticoids) and their respective receptors, tissue-
               specific responses are triggered as well as the general modulation of the immune system and inflammation.
               Studies have confirmed that stress hormones are critical for the initiation and development of multiple
               diseases [2,3,52] , but the impact of psychological stress on keloid pathogenesis has been neglected.


               As for keloid patients, the original trauma, uncomfortable feelings, together with the cosmetic concerns
               are all potent and constant underlying stressors, which make them very likely to be trapped in a stress-
               intensive state. Therefore, psychological stress is a pivotal and inevitable element that should be taken into
               consideration in formulating optimal treatment regimens. In view of the reviewed literature, especially with
               regards to stress hormone-induced cellular and physiological changes observed during psychological stress,
               we advance the hypothesis that stress hormones (NE, E) may participate in the keloid formation by: (1)
               increasing the expression of keloid-associated IL-6 via activating β-ARs; (2) triggering growth responses of
               fibroblasts and symptoms(pain and pruritus) in scar tissues by directly activating α-ARs; (3) exacerbating
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