Toll-Like Receptor 4 Expression in Human Breast Implant Capsules: Localization and Correlation with Estrogen Receptors

Sir: We read with great interest the article by Segreto et al. that was published in March of 2016 investigating the expression of toll-like receptor 4 in breast implant capsules and its relationship with estrogen receptors.1 The pathogenesis of capsular contracture has been unclear. The authors should be applauded for the choice of subject and for this clear, well-written study. However, we think that the study has some parts that need to be clarified and some points that need to be discussed methodologically. The authors reported the results of immunohistochemical and immunofluorescence staining with four antibodies (i.e., α-smooth muscle actin, toll-like receptor 4, estrogen receptor-α, and estrogen receptor-β) of 32 capsules that were harvested during surgery for expander substitution with definitive implant. The time from implantation ranged from 4 to 24 months, and 10 specimens were taken from Baker grade I, seven were taken from grade II, 12 were taken from grade III, and three were taken from grade IV. As a result, they demonstrated that estrogen receptor-β positively correlated with toll-like receptor 4 and α-smooth muscle actin expression, but there was no statistically significant correlation between toll-like receptor 4 and contracture grade. Thus, they concluded that these findings add further evidence for the involvement of these receptors in the pathogenic process, as they are mainly expressed when fibroblasts have differentiated into myofibroblasts. In a similar study published in 2014 by the same authors, a lower contracture severity was demonstrated in patients who underwent antiestrogenic therapy.2 The authors found a negative correlation between estrogen receptor-β and capsular thickness (reported in microns), which was presumed to be caused by down-regulation of proliferation induced by this receptor, and they stated that in the human mammary gland, 17β-estradiol induces cellular proliferation by means of estrogen receptor-α, whereas it inhibits proliferation and promotes differentiation through estrogen receptor-β.2 Likewise, another study reported that toll-like receptor 4 becomes up-regulated within the first days after injury and slowly decreases to baseline.3 Thus, it could be concluded that more estrogen results in more capsular thickness in the early phases and then down-regulation of estrogen receptor-β and toll-like receptor 4, which was demonstrated in the current study. We think that it may be a good choice to report the relationship between toll-like receptor 4 and capsular thickness, which is a quantified measurement, rather than capsular grade, which is a qualified method, to clarify the correlation between toll-like receptor 4 and the myofibroblasts, because it is reported that the α-smooth muscle actin–positive myofibroblasts made up approximately 27 percent of the capsule thickness.4 In addition, if the authors’ aim was to evaluate toll-like receptor 4 expression in human breast implant capsules and its possible correlation with estrogen receptor expression, it would be more appropriate to classify the subjects according to premenopausal and postmenopausal groups, which could be seen as increased and depleted endogenous estrogen expression at the time of expander implantation. Thus, we could comment on the effect of estrogen in estrogen receptors and maybe in toll-like receptor 4. As the authors highlighted, unlike other toll-like receptors, toll-like receptor 4 may also be activated by endogenous ligands, as demonstrated in a variety of studies, and possibly by extracellular proteins and/or cytokines. Stimulation of toll-like receptor plays an important role in promoting normal wound healing, but excessive toll-like receptor signaling might contribute to maladaptive or hypertrophic wound healing and fibrosis.5 This study could give us good ideas for further studies on the pathophysiology of capsule formation in breast implants, in which we have also started a multicenter study on the same issue; however, rather than reporting only the existence of a positive correlation between toll-like receptor 4 and estrogen receptor-β in breast capsule specimens, an extended study will be more informative to demonstrate the role of the native immune system in capsule formation. DISCLOSURE The authors confirmed no funding supporting the work and no financial interest or conflict of interest to declare in relation to the content of this communication. Özlem Çolak, M.D.Istanbul Okmeydani Training and Research HospitalPlastic, Reconstructive, and Aesthetic Surgery ClinicIstanbul, Turkey Kadri Ozer, M.D.Aydin State HospitalPlastic, Reconstructive, and Aesthetic Surgery ClinicAydin, Turkey Adile Dikmen, M.D.Ankara Training and Research HospitalPlastic, Reconstructive, and Aesthetic Surgery ClinicAnkara, Turkey