Investigating the role of immune-olfactory signaling in inflammatory skin disease
Grantee: Joshua Moreau, Assistant Professor, Oregon Health and Science University
Amount: DKK 3,717,163
Grant category: Serendipity Grants
Year: 2025
Geography: USA
Organisms are continuously bathed in a rich milieu of olfactory compounds. Defined by their ability to elicit the sense of smell, these molecules, and the receptors that sense them, have profound biological importance. Humans have hundreds of olfactory receptors, but paradoxically these are often expressed outside of the nasal cavity and on immune cells. Their function in these contexts is almost entirely unknown. The serendipitous finding illustrates that: a) olfactory receptors are enriched in inflamed skin and on lesion infiltrating lymphocytes; and b) odorants directly modulate lymphocyte function. Understanding the role and molecular mechanisms of these pathways in inflammation may open new avenues for treating skin disease with promise for targeted topical approaches.
To explore this serendipitous finding, the research project will combine in vivo models of skin inflammation with expertise in multiomic analyses of hidradenitis suppurativa (HS) and pyoderma gangrenosum (PG) patient tissues. The study will determine if exposure to olfactory molecules modulates skin inflammation in vivo, functionally dissect immune cell intrinsic olfactory signaling, and identify signatures of pathway activity in HS and PG.
This work will provide insight into the fundamental biology of immune-olfactory signaling and determine if there is functional relevance for skin inflammation. The project will also test the implications for HS and PG, where novel therapeutic approaches are urgently needed.
Role of JNK and type 1 interferon signaling in Hailey-Hailey disease
Grantee: Cory Simpson, Assistant Professor, University of Washington
Amount: DKK 3,988,727
Grant category: Serendipity Grants
Year: 2025
Geography: USA
Hailey-Hailey disease (HHD) is a rare genetic disorder causing recurrent skin blistering and infections. Despite linkage to heterozygous (HET) mutations depleting the SPCA1 Golgi calcium pump 25 years ago, HHD lacks proven therapies. Cory Simpson’s LEO-funded research using in vitro HHD models led to two serendipitous discoveries that fuel this grant: (1) a JNK inhibitor intended as a negative control markedly strengthened adhesion among HET keratinocytes; (2) this led them to re-analyze RNAseq data, which revealed an overlooked aberration that may make HHD patients susceptible to pathogens like herpes simplex virus (HSV). Previously they focused on upregulated pathways amenable to drug inhibition; re-examining downregulated genes in HET cells, they found suppression of type 1 interferon (IFN) signaling. These data support their hypothesis that stress-induced JNK activation upon Golgi protein misfolding in HET keratinocytes weakens cell junctions to cause blistering and dampens IFN responses, facilitating viral infection.
To test these ideas, Cory Simpson required new tools and collaborators in immunology and virology, who provided biosensors to visualize and quantify JNK and type 1 IFN activity along with GFP-tagged HSV to infect the HHD models.
The planned work will test if modulating JNK or type 1 IFN in the HHD model can bolster epidermal integrity and suppress viral infection. Thus, the project has potential to directly impact treatment of patients with this orphan disease.