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Page 6 of 10 Yang et al. Plast Aesthet Res 2020;7:34 I http://dx.doi.org/10.20517/2347-9264.2020.24

factor-β (TGF-β), platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) [46,47] , which
are critical for the migration, proliferation and collagen synthesis of fibroblasts. Moreover, previous studies
have demonstrated that the expression of several immune-related genes was also dysregulated in keloid
tissues [48,49] .

The elevated C-reactive protein (CRP, a marker of inflammation) plasma concentration in caregivers
of Alzheimer’s patients [50,51] also implied that psychological stress was a potent inducer of the chronic
inflammation state. Analysis of stress models revealed that stress hormones (NE, E, glucocorticoid) have
[52]
detrimental effects on immune functions as well as the inflammation process from various aspects . Here
are some keloid-associated inflammatory molecules or mechanisms that have been identified dysregulated
in stressed conditions.

TGF-β
TGF-β is probably the most fibrogenic factor associated with keloid formation by acting as a strong
[53]
chemotactic agent for fibroblasts and increasing cell rigidity through TGF-β1 receptor-smooth muscle
[54]
actin axis . It is also known as a regulatory resolution factor that can induce remodeling within sites of
[15]
damaged tissues upon mood disorder-associated inflammatory processes .
In the inflammatory and proliferative phase, degranulation of platelets releases and activates several
[44]
fibrogenic growth factors and chemotactic agents including TGF-β1 and TGF-β2 , to increase the
corresponding receptors and responsiveness compared to fibroblasts from normal tissues [55-58] . Although
there is no direct evidence that stress hormones can enhance the efficacy of TGF-β in keloids, it is
nevertheless clear that TGF-β plays a pivotal role in keloid formation and stress-derived inflammatory
conditions.

The cells and cytokines
CD4 T cells express T helper lymphocyte (Th)1 or Th2 responses, while glucocorticoids are thought
to cause a shift from Th1 to Th2 cytokines by downregulating Th1 cytokines and upregulating Th2
[59]
cytokines . Th1 responses produce interferons and IL-12 and are thought to be related to the attenuation
of fibrogenesis, whereas Th2 responses (IL-4, IL-5, IL-10 and IL-13. IL-1, and IL-6) are generally related to
fibrogenesis, among which IL-4, IL-5, IL-6, and IL-13 are thought to be essential for promoting fibroblast
recruitment and proliferation, ECM deposition, angiogenesis and re-epithelialization [16,17,47] (except for
IL-10, which are mainly related to anti-fibrosis [60-62] . In a published report, stress was associated with a
decrease in IL-2 receptor (IL-2R) mRNA levels and the protein expression in peripheral blood leukocytes
[63]
compared to the baseline . In a longitudinal study over 6 years, caregivers and former caregiver’s (a kind
of stress model) showed elevated plasma IL-6 levels that increased at a rate four times faster than those of
[50]
age-matched controls . Elevation of serum IL-6 (a marker of inflammation) levels have been previously
[64]
described in both chronically stressed older adults and keloid patients. Since a clear NE-IL-6 pathway has
[4,5]
been identified in NSCLCs and ovarian cancer , we presumed that a similar NE-induced IL-6 elevation
might exist in keloid. Stress hormones and related receptors could thus serve as feasible therapeutic targets.

Macrophages and treg cells
Macrophages are divided into two subsets, the IL-12- and inducible nitric oxide synthase (iNOS)-expressing
[65]
M1 type and the IL-10- and TGF-β-expressing M2 type . The classically-activated (M1) cells that secrete
pro-inflammatory cytokines, whereas alternatively-activated (M2) cells that foster tissue repair and
regeneration [66,67] . It was found that M1-associated genes, including iNOS and IL-12, were less elevated in
[68]
keloid tissues than M2-associated genes, including IL-10 and TGF-β , suggesting that macrophages in
keloids were shifted toward the M2 polarization.