Project

Discipline

Inflammation-IL1-acne

Lead
The role of the inflammasome and the subsequent release of the potent inflammatory cytokine IL-1 are investigated in the setting of inflammatory diseases including acne and acne-like eruptions.
Lay summary
Innate immunity, is an inborn immediate "first line" of response to signals resulting from pathogens and danger. Recently it has been shown that certain intracellular receptors (Nod-like receptors, NLRs), can assemble into high-molecular platforms called ‘‘inflammasomes’’, that control the maturation and secretion of selected pro-inflammatory interleukins such as IL-1b and IL-18, whose activities direct host responses to infection and injury. Based on the fact that deregulation of the inflammasome and IL-1b has been linked to an autoinflammatory syndrome associating pyogenic arthritis, pyoderma gangrenosum and acne, named PAPA syndrome, and the fact that acne is characterized by neutrophilic infiltration of the skin (pilosebaceous unit), we propose to investigate if the inflammasome and IL-1b are involved in the pathogenesis of acne and the potentially related acneiform adverse cutaneous reactions occurring in cancer patients receiving EGFR inhibitors The characterization of innate immunity pathways involved in these two inflammatory skin diseases will lead to a better understanding of the pathogenesis and help us identify optimal therapeutic targets.

Direct link to Lay Summary

Last update: 07.10.2013

Number	Title	Start	Funding scheme

Innate immunity, is an inborn immediate "first line" of response to signals resulting from pathogens (PAMPs) and danger (DAMPs). Recently it has been shown that certain Nod-like receptors (NLRs), and specifically members of the NLRP (also called NALP) family, can assemble into high-molecular weight, caspase-1-activating platforms called ‘‘inflammasomes’’, that control the maturation and secretion of selected interleukins such as IL-1ß and IL-18, whose proinflammatory activities direct host responses to infection and injury. Interestingly, certain inherited genetic variants of constituents of the innate immune system can result in autoinflammatory diseases are often characterized by sterile neutrophilic tissue inflammation, and this can be recapitulated in gene targeted mice harboring equivalent mutations (NLRP3) to those found in Cryopyrin Associated Periodic Syndrome (CAPS) patients. We have recently shown that inflammasome assembly in keratinocytes can be induced by contact allergens and contribute to inflammation in a mouse model of contact dermatitis. Furthermore, we demonstrated that the inflammasome acts as a master switch between tolerance and sensitization to irritant chemicals in the skin, and plays a crucial role in the onset of graft versus host disease following bone marrow transplantation. Based on the fact that dysregulation of the inflammasome and IL-1ß has been linked to an autoinflammatory syndrome associating pyogenic arthritis, pyoderma gangrenosum and acne, named PAPA syndrome, and the fact that acne is characterized by neutrophilic infiltration of the skin (pilosebaceous unit) a feature observed in transgenic mice overexpressing the inflammasome component NLRP3, we propose to investigate if the inflammasome and IL-1ß are involved in the pathogenesis of acne and the potentially related acneiform adverse cutaneous reactions to anti-EGFR targeted treatments. Preliminary experiments performed in our lab enabled us to demonstrate that Propionibacterium acnes (P. acnes) - a pathogenic microorganism in acne patients - can potently trigger the production and secretion of the mature form of IL-1ß in cells of monocytic lineage via an inflammasome-dependent pathway in vitro. Furthermore, we could show in a mouse model of P. acnes infection, that the inflammatory skin response is significantly abrogated in mice deficient for the inflammasome components NLRP3 and ASC, as well as in the case of treatment with recombinant IL-1 RA (Anakinra). In the submitted grant application, we propose to dissect distinct aspects of the innate immune response occurring in the skin in response to the microorganism P. acnes as well as in response to EGFR inhibition, two situations relevant to clinical diseases with high morbidity, namely acne and the acneiform skin eruption occurring in cancer patients receiving EGFR inhibitors. We propose to combine i) genomic analyses focused on genes involved in innate immunity, combined with appropriate protein-analysis in both human biopsies and lesional skin of relevant mouse models; ii) detailed in vitro studies focused on the inflammasome, TLR- and IL-1-signaling pathways using antigen-presenting cells and keratinocytes from murine or human origin with targeted knock-down of selected molecules; and iii) in vivo experiments using appropriate mouse models of disease, and mouse strains deficient for key components of the innate immune response. The characterization of innate immunity pathways involved in these two inflammatory skin diseases will lead to a better understanding of the pathogenesis and help us identify optimal therapeutic targets