RESUMEN
BACKGROUND: Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea. OBJECTIVE: We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system. METHODS: Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel. RESULTS: AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment. LIMITATIONS: Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA. CONCLUSIONS: These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Ácidos Dicarboxílicos/uso terapéutico , Calicreínas/metabolismo , Rosácea/tratamiento farmacológico , Rosácea/metabolismo , Serina Proteasas/metabolismo , Administración Tópica , Adulto , Anciano , Animales , Péptidos Catiónicos Antimicrobianos/efectos de los fármacos , Péptidos Catiónicos Antimicrobianos/genética , Biomarcadores/metabolismo , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Estudios de Cohortes , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Geles , Humanos , Calicreínas/efectos de los fármacos , Calicreínas/genética , Queratinocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Factores de Riesgo , Rosácea/diagnóstico , Serina Proteasas/efectos de los fármacos , Serina Proteasas/genética , Resultado del Tratamiento , CatelicidinasRESUMEN
Inflammation under sterile conditions is a key event in autoimmunity and following trauma. Hyaluronan, a glycosaminoglycan released from the extracellular matrix after injury, acts as an endogenous signal of trauma and can trigger chemokine release in injured tissue. Here, we investigated whether NLRP3/cryopyrin, a component of the inflammasome, participates in the inflammatory response to injury or the cytokine response to hyaluronan. Mice with a targeted deletion in cryopyrin showed a normal increase in Cxcl2 in response to sterile injuries but had decreased inflammation and release of interleukin-1beta (IL-1beta). Similarly, the addition of hyaluronan to macrophages derived from cryopyrin-deficient mice increased release of Cxcl2 but did not increase IL-1beta release. To define the mechanism of hyaluronan-mediated activation of cryopyrin, elements of the hyaluronan recognition process were studied in detail. IL-1beta release was inhibited in peritoneal macrophages derived from CD44-deficient mice, in an MH-S macrophage cell line treated with antibodies to CD44, or by inhibitors of lysosome function. The requirement for CD44 binding and hyaluronan internalization could be bypassed by intracellular administration of hyaluronan oligosaccharides (10-18-mer) in lipopolysaccharide-primed macrophages. Therefore, the action of CD44 and subsequent hyaluronan catabolism trigger the intracellular cryopyrin --> IL-1beta pathway. These findings support the hypothesis that hyaluronan works through IL-1beta and the cryopyrin system to signal sterile inflammation.