Rosacea pathogenesis and therapeutics: current treatments and a look at future targets

Abstract

Rosacea is a chronic inflammatory skin condition associated with a significant health and economic burden from costs and loss of productivity due to seeking medical treatment. The disease encompasses multiple phenotypic manifestations involving a complex and multi-variate pathogenesis. Although the pathophysiology of rosacea is not completely understood, ongoing research is continually elucidating its mechanisms. In this review, current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system. More specifically, the cathelicidin pathway, transient potential receptor channels, mast cells, and the NLRP3 inflammasome pathway are various targets of current pharmacologic regimens. Future therapies may seek different mechanisms to act on current treatment targets, like the potential use of JAK/STAT inhibitors in ameliorating skin barrier dysfunction or TLR antagonists in alleviating cathelicidin mediated inflammation. Other potential treatments aim for entirely different molecular targets such as microvesicle particle mediated local and systemic inflammation. Ultimately rosacea is associated with a significant health and economic burden which warrants deeper research into its pathogenesis and resultant new treatment discovery.

Keywords: cathelicidin; inflammatory; pathogenesis; pharmacotherapeutics; rosacea.

Figure 1

Proposed mechanism of rosacea pathogenesis. The flow diagram depicts inciting factors in green and molecular pathways in grey which ultimately leads to symptoms and rosacea phenotypes shown in blue. Some triggers of rosacea include PAMP’s, heat, and UVB. Major molecular players originating from triggers include TLR2, TRPV/TRPA, and MVP’s. TLR’s are sensors for PAMPs which act as triggers and induce KLK5 activation leading to the cleavage of cathelicidin LL-37 into pro-inflammatory fragments. Additionally, mTORC1 has been shown to interact with LL-37 in a feedback loop. Downstream effects of LL-37 fragments include mast cell activation, angiogenic chemokine release, and NLRP3 inflammasome activation. MRGPRX2 is a GPCR activated by LL-37, modulated by β-arrestin-2, and mediates non-IgE mast cell degranulation. Mast cell activation and degranulation is implicated in ETR, phymatous, and PPR rosacea phenotypes. Angiogenic chemokines include VEGF and lead to angiogenesis in the skin of rosacea patients. NLRP3 plays a pivotal role in innate and inflammatory signaling and functions through various cytokines, such as IL-1 $\beta$ and IL-18. These cytokines play a pivotal role in skin inflammatory conditions with proven implications in PPR. Heat is another trigger, shown to act through the nociceptive TRPV/TRPA sensors leading to release of vasoactive peptides causing flushing and stinging. UVB is also a trigger that’s associated with MVP release from skin keratinocytes. MVP’s function through the pro-inflammatory mediator PAF causing mast cell degranulation. Skin barrier dysfunction is another inciting factor of rosacea and is associated with Demodex mite skin colonization and upregulation of STAT transcriptions factors. Skin barrier dysfunction leads to immune cell infiltration and skin inflammation in rosacea.

Figure 2

Proposed rosacea pathogenesis with potential drug targets. Current therapeutics are depicted in yellow with future therapeutic possibilities depicted in red. Aza, carvedilol, and isotretinoin are three current therapeutics that act on the cathelicidin pathway. Isotretinoin inhibits sebaceous gland function and downregulates the TLR2 pathway, carvedilol has been shown to downregulate TLR2/KLK5/LL-37 pathway, and Aza has been shown to downregulate KLK5. Botox and cromolyn are two current therapeutics that function via mast cell mediation. Botox has been shown to decrease mast cell degranulation in human and mouse models, and cromolyn functions as a mast cell stabilizer. Brimonidine and oxymetazoline are two current therapeutics that act as alpha-sympathetic receptor agonists in the treatment of ETR. Brimonidine acts via alpha-2 agonism and oxymetazoline acts via alpha-1 agonism. EGCG, rapamycin, celastrol, and thalidomide are four potential therapeutics that act on both downstream and upstream targets of LL-37. Rapamycin via mTORC1 modulation and EGCG has been shown to induce keratinocyte autophagy via a similar mTOR mediated pathway. Celastrol and thalidomide function by inhibiting the downstream effects of NF-kβ including release of various cytokines and chemokines. HCQ has been shown to suppress mast cell infiltration via hypothesized mitigation of LL-37 mediated activation through the GPCR MRGPRX2. SSA is hypothesized to treat rosacea via inhibition of NLRP3 inflammasome assembly. Lastly, TCA’s and paroxetine are hypothesized to block the release of MVP’s from keratinocytes thereby mitigating mast cell degranulation from PAF (Tricyclics = tricyclic antidepressants, HCQ = hydroxychloroquine, EGCG = epigallocatechin-3-gallate, SSA = supramolecular salicylic acid, AzA = azelaic acid).