Tranilast Directly Targets NLRP3 to Protect Melanocytes From Keratinocyte-Derived IL-1β Under Oxidative Stress

Abstract

The activation of NLRP3 inflammasome-IL-1β pathway in keratinocytes contributes to the melanocyte death via autoimmunity-dependent manner in vitiligo. As a safe small-compound drug employed frequently in clinic, tranilast (TR) is newly reported to block the activation of NLRP3 inflammasome in macrophage. Nevertheless, whether keratinocyte-derived IL-1β damages melanocytes in an autoimmunity-independent way and whether TR could ameliorate the melanocyte damage via inhibiting the NLRP3-IL-1β pathway in keratinocyte still are not clear. In the present study, we initially found that TR could impede the secretion of IL-1β from keratinocytes by interfering the NLRP3 oligomerization. More importantly, we illustrated that TR could decrease the melanocyte apoptosis, improve the melanogenesis, and have the capacity to optimize the melanosome translocation by abolishing the keratinocyte-derived IL-1β. Additionally, TR could mitigate the secretion of inflammatory cytokines such as IL-6, IL-8, TNF-α, and IL-18 in keratinocytes under oxidative stress. In short, our data indicate that IL-1β plays detrimental roles in the melanocyte survival, melanogenesis, melanosome translocation and the secretion of inflammatory cytokines, and TR could be a promising therapeutic strategy in vitiligo by attenuating the keratinocyte-derived IL-1β under oxidative stress.

The two faces of mast cells in vitiligo pathogenesis

“…Promising results of clinical trials for vitiligo using histamine solution also support the histamine induction of hypermelanosis in the surrounding skin in vitiligo [25]. Another possible new treatments are under investigation at present targeting epidermal keratinocytes [26][27][28][29][30].…”

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

“…Although, NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes [ 87 , 96 , 108 ] expression of NLRP3 can also be detected in basal keratinocytes ( Figure 2 A) [ 128 , 129 ]. NLRP3 activation in human keratinocytes can be initiated by various signals [ 128 , 129 ] but without a need for a priming signal. Human keratinocytes respond to viral RNA with caspase-1 activation and subsequent IL-1β and IL-18 release, which is dependent on NLRP3 [ 129 ].…”

“…Interestingly, intact skin of both human and mouse produce the same mediators upon the NLRP1 activating UVB exposure, but while in humans the process is mediated by NLRP1 in keratinocytes, in mouse skin the immune cells are responsible for this phenomenon [ 87 ]. Similarly, NLRP3 is also expressed and functional in human keratinocytes [ 128 , 129 ], but not in murine epidermis [ 171 ]. In human cells, NLRP10 regulates inflammasome activation [ 152 , 154 ], while Nlrp10 knock-out mice respond normally to inflammasome activation [ 155 , 156 ], suggesting a difference in function between the human and mouse proteins.…”

Ginsenoside Rk1 protects human melanocytes from H2O2‑induced oxidative injury via regulation of the PI3K/AKT/Nrf2/HO‑1 pathway

“…Oxidative stress (OS), defined as an imbalance between radical-generating and radical-scavenging activity, has been associated with a variety of diseases, including hypertension, diabetes, cancer and cardiovascular diseases (2,3). An increasing number of studies have indicated that the pathogenesis of vitiligo is associated with OS-mediated toxicity in melanocytes (4)(5)(6)(7). Previous studies have indicated that the state of OS commonly results in increased intracellular reactive oxygen species (ROS) production, which influences various signaling pathways leading to inhibition of melanin synthesis, destruction of cell structures and reduced survival of melanocytes (8)(9)(10)(11).…”