UC Davis

Atopic dermatitis (AD) is a chronic, recurring, inflammatory condition of the epidermis characterized by pruritis and itching, with clearly delineated margins, that affects approximately 20% of children worldwide. The cause of AD is not understood but in recent years it has become clear that the symptoms of AD are driven by disrupted balances in cytokine and chemokine signaling, immune cell recruitment, activation, and phenotype, genetics, microbial dysregulation, and causal or symptomatic barrier dysfunction. Following an “Outside-in” model, AD is caused by disrupted barrier function of the epidermis, often due to mutations in genes coding proteins essential for proper function of the cornified envelope. This leads to ingress of exogenous antigens which then trigger inflammation driven by Th2 cells, a myriad of resident immune cells, and keratinocytes. Following an “inside-out” model of AD progression, immune dysregulation, potentially due to epigenetic mutations in cells such as CLA+ T memory cells, leads to rampant inflammation and degradation of the cornified envelope by epidermal basification and impaired barrier protein secretion by inflamed keratinocytes.One potential way to halt this inflammatory loop is via inhibition of the MAP kinase pathway, which promotes secretion inflammatory cytokines via stabilization of mRNA. Our lab has developed a family of MAP kinase inhibitor peptides (MK2i) that may prove useful in this endeavor. However, like all unmodified peptides, their effectiveness is limited by short half-life in vitro and in vivo. In this work, we introduce a novel nanoparticle platform consisting of glycosaminoglycans electrostatically coupled with MK2i and show that they enhance efficacy of MK2i in reducing inflammation in an in vitro model of keratinocyte inflammation by protecting it from enzymatic degradation. We also assess the stability of these new nanoparticles and delve into the differences between two synthesis methods. Lastly, we use sulfated hyaluronic acid at various molecular weights as a dermatan sulfate analog to explore the role sulfation and molecular weight play in particle formation and ascertain if this nanoparticle technology can be used with other peptides.