Abstract
Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding and/or inflammation of the skin. Despite intensive research, treatment for KD remains empirical and unsatisfactory. Activation of the renin-angiotensin system (RAS) leads to fibrosis in various organs through its direct effect and the resultant hypertension, and activation of the immune system. The observation of an increased incidence of KD in dark-skinned individuals who are predisposed to vitamin D deficiency (VDD) and hypertension, and the association of KD with hypertension and VDD, all of which are associated with an elevated activity of the RAS, provides clues to the pathogenesis of KD. There is increasing evidence implicating embryonic-like stem (ESC) cells that express ESC markers within keloid-associated lymphoid tissues (KALTs) in keloid lesions. These primitive cells express components of the RAS, cathepsins B, D, and G that constitute bypass loops of the RAS, and vitamin D receptor (VDR). This suggests that the RAS directly, and through signaling pathways that converge on the RAS, including VDR-mediated mechanisms and the immune system, may play a critical role in regulating the primitive population within the KALTs. This review discusses the role of the RAS, its relationship with hypertension, vitamin D, VDR, VDD, and the immune system that provide a microenvironmental niche in regulating the ESC-like cells within the KALTs. These ESC-like cells may be a novel therapeutic target for the treatment of this enigmatic and challenging condition, by modulating the RAS using inhibitors of the RAS and its bypass loops and convergent signaling pathways.
Highlights
Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding such as ear piercing, surgery and burns, or inflammation such as acne and herpes zoster infection [1,2,3]
We have recently demonstrated an embryonic stem cell (ESC)-like population within keloid-associated lymphoid tissues (KALTs) that expresses components of the renin-angiotensin system (RAS) [26], cathepsins B, D, and G which constitute bypass loops of the RAS [42], and vitamin D receptor (VDR) [27]
We have recently demonstrated the expression of pro-renin receptor, angiotensin-converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), Angiotensin II receptor 2 (ATIIR2) on the endothelium of the microvessels and perivascular cells within the KALTs [26]
Summary
Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding such as ear piercing, surgery and burns, or inflammation such as acne and herpes zoster infection [1,2,3]. KLs, especially larger lesions, may cause physical disability and psychological sequelae with impaired quality of life for affected individuals [6, 8]. Current first-line treatment for KD includes intralesional corticosteroid injections [13], topical 5-fluorouracil [14], surgical excision with intra-operative steroid injection [15] or postoperative radiotherapy [16], laser therapy [17], cryotherapy [18], and silicon occlusive dressing [15] These empirical treatments for KD remain unsatisfactory [13], with high recurrence rates of 45–100% following surgical excision without adjuvant therapy [10], underscoring the need for understanding the pathogenesis of this enigmatic condition. In this review we discuss growing evidence supporting an embryonic stem cell (ESC)-like origin of KD, and the complex interactions these primitive cells have with the RAS, hypertension, VD-related pathways and the immune system, to elucidate the pathogenesis of this challenging condition
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