Evaluation of the Role of High-Mobility Group Box 1 Protein in Patients With Keloids

A Case Control Study

Omar Ahmad Azzam, MD; Marwa Salah El-Mesidy, MD; Moataz Maher Kamel, MD; Amira Basyouny Nouh, MBBch


Wounds. 2019;31(7):179-183. 

In This Article


Keloids have remained a challenge for physicians and a significant quality of life issue for many patients. Keloids cause cosmetic problems as well as pain, pruritis, and contractures.[12] Despite advances over the past century, many patients still experience the negative effects of excessive scarring and presently are without effective treatment.

There are numerous modalities for treating keloids, but all have unsatisfying results for patients and physicians. Intralesional corticosteroid may improve scar pliability, diminish its volume and height, and reduce scar-related itching and pain.[13] The main problem of this treatment is the high frequency of side effects, up to 63%,[14] such as hypopigmentation, skin atrophy, telangiectasia, ineffectiveness, injection site pain, and osteoporosis secondary to a large injection area.[15] Cryotherapy is another common therapeutic modality with side effects that include permanent hypo- and/or hyperpigmentation, moderate skin atrophy, blistering, and postoperative pain.[13] Wound ulceration, hyperpigmentation, and pain are potential complications of treatment with fluorouracil.[16] Bleomycin is an uncommon modality for keloids,[17] and imiquimod adverse effects include irritation and hyperpigmentation.[18] The neodymium-doped yttrium aluminum garnet laser (1064 nm), flashlamp-pumped pulsed dye laser (585 nm-595 nm), and carbon dioxide laser have been used frequently in the treatment of keloids;[19] however, none of the available laser modalities produced a satisfactory response until 2011.[20] Despite the numerous modalities for the treatment of keloids, there is no satisfactory therapeutic regimen because the exact pathogenesis is still unclear.

High-mobility group box 1 protein has dual functions. As an intracellular transcription factor, HMGB1 binds to bent DNA to promote the assembly of nucleoprotein complexes, which is critical in the process of transcription, recombination, replication, and repair. As an extracellular mediator, HMGB1 acts as a potent inflammatory cytokine.[4] The release of HMGB1 occurs actively by stimulated monocytes and macrophages and passively by necrotic/damaged cells.[5] It exerts its effects by binding to cell surface receptors, particularly the receptors for RAGE, TLR2, and TLR4.[21]

Several studies have discussed the potential role of HMGB1 in wound healing, such as increasing the viability, proliferation, and migration of keratinocytes and fibroblasts.[4,7] In addition, adding HMGB1 to diabetic murine skin with reduced HMGB1 levels and altered wound healing increased fibroblast migration and wound closure rates.[7]

The role of HMGB1 in keloids was investigated in the present study. Because this protein is known to have a role in wound healing and is found in low levels in diabetic skin, it was hypothesized that HMGB1 elevation might play a role in keloid pathogenesis. Perhaps this could be a target for developing novel HMGB1 inhibitors for the prevention and/or reversal of keloid formation.

Blood samples were taken from 40 keloid cases and 40 controls to compare the level of HMGB1 in both groups and correlate the level with the severity and duration of keloids. A statistically significant elevation of HMGB1 in the case group compared with the control was found (P = .001), and the level of HMGB1 was found to positively correlate with the severity but not with skin type or duration. To the best of the authors' knowledge, this is the first study comparing the levels of HMGB1 in patients with keloids and healthy controls.

Considering that HMGB1 plays a role in wound healing and excessive scarring, it was found to be elevated in other fibrotic diseases such as scleroderma, cystic fibrosis, and pulmonary fibrosis.[22] Entezari et al[23] reported that inhibiting HMGB1 activity is beneficial to treat fibrotic diseases. Moreover, Lee et al[24] suggested HMGB1 promotes wound healing by inducing the proliferation and migration of fibroblasts.

Trauma and tissue damage trigger an inflammatory response, which is required for post injury tissue repair. Inflammation following tissue damage is a dynamic process driven by numerous inflammatory mediators.[25] The role of HMGB1 in inflammation as a chemoattractant for inflammatory cells has been defined, but the specific receptor (eg, for RAGE, TLR2, or TLR4) involved in this phenomenon is not clear.[4]

In addition, HMGB1 directly contributes to vessel formation through promoting endothelial cell (EC) proliferation, migration, and sprouting. Besides, HMGB1 may promote the release of proangiogenic cytokines from ECs and macrophages.[26]

Emerging evidence indicates that HMGB1, a pluripotent mediator, contributes to many fibrotic diseases, and may be a promising therapeutic target for such diseases.[23] Based on these facts, it was suggested that HMGB1 also might play a role in the excessive scarring such as keloids. The excess production of collagen seen in keloids could result from excess HMGB1 or increased responsiveness of fibroblast receptors to HMGB1, suggesting similar effects of HMGB1 and TGF-β on the induction of keloids. This is why the present authors recommend examining the level of these receptors and their sensitivity in future studies. The elevated level of HMGB1, along with the positive correlation in keloid severity, may lead to the possibility of using HMGB1-blocking agents in the treatment of patients in whom other forms of therapy would be impractical. In addition, the HMGB1 protein can be targeted using anti-HMGB1 antibody.[27]

There is no single mode of delivery for treatment, and further studies are needed to choose the best way to prevent and treat keloids without affecting the role of HMGB1 in transcription. It is possible that intralesional injection of HMGB1-targeted therapies in already formed keloids could help treatment or that intralesional injection in a postoperative wound could prevent further keloid appearance in a patient with a known history of keloid formation. The possibility of systemic delivery of a HMGB1-blocking agent to help individuals with spontaneous keloid formation still needs to be explored. However, future studies should aim to help treatment of excessive scarring with HMGB1 while considering its 2 dramatically opposed functions in the body as a biologically intrinsic requisite factor and as a proinflammatory cytokine. Though inhibiting the proinflammatory effects of HMGB1 is a therapy goal, research should recognize its essential nuclear function.