Our Community Blog Understanding inflammasomes in hidradenitis suppurativa: key protein complexes that may lead to chronic inflammation in the skin April 2021 Dr Daniel Johnston is the AbbVie Newman Fellow in Dermatology at University College Dublin. He and his supervisors, Prof. Des Tobin and Prof. Brian Kirby of the Charles Institute of Dermatology and St Vincent’s University Hospital, have been awarded a British Skin Foundation Small Grant Award entitled “An analysis of inflammasome activity in the skin and blood of patients with hidradenitis suppurativa”. This work will be carried out in collaboration with Dr Rebecca Coll of Queen’s University, Belfast. Here Daniel explains what they hope to achieve by studying this group of potent inflammatory mediators in the disease. Above image: Dr Daniel JohnstonTop image: Charles Institute of Dermatology, University College Dublin What’s the problem with hidradenitis suppurativa? Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease affecting areas where skin rubs together, including under the arms and around the groin. It is currently thought to originate when a hair follicle becomes blocked and then bursts, setting off a chronic inflammatory immune system response we don’t fully understand. During a flare, this manifests as painful boils and abscesses which can weep odorous fluids, causing significant pain and embarrassment. HS affects between 1-4% of the general population, and patient quality of life is even more significantly impaired compared to other skin diseases such as psoriasis, with social isolation and depression very common among HS patients. In more severe HS, significant rope-like scarring can develop, further impacting the patients’ quality of life. Treatment options for HS remain limited and therapy is often unsatisfactory. In order to design better treatments for HS, there is a need to better understand the disease itself and the factors that initiate it and make it a chronic condition. Cytokines and inflammation Immune dysfunction is one of the factors responsible for triggering HS and causing long-term skin inflammation. HS lesions are infiltrated by immune cells that release inflammatory proteins termed cytokines. Cytokines are essential for immunity to bacteria and viruses, but when they are present at excessive levels like in HS they cause problems, as they also do in other inflammatory disease like psoriasis and rheumatoid arthritis. The current best-in-class treatment for HS targets a cytokine termed TNF-a, and it is likely that other cytokines will also make valuable drug targets. Multiple studies, including our own, have demonstrated that the pro-inflammatory cytokine IL-1β is overproduced in HS skin and may be a key part of early HS pathology. In HS, it is hypothesized that IL-1β is released by immune cells in response to sensing material released from the blocked hair follicle, which may include bacteria and components of dead skin cells. IL-1β is a very potent cytokine which clinicians believe may be a very promising target in HS. It is important to understand why IL-1β is elevated in HS patients to best achieve success in this research effort. Crucially, both IL-1β release and a form of inflammatory cell death termed pyroptosis are controlled by cellular machinery called the inflammasomes. Inflammasomes, IL-1β and HS Inflammasomes are a recently discovered group of multi-protein complexes that cells use to sense danger signals in their environment. Having sensed the danger via a pattern recognition receptor, the inflammasome then responds by activating key proteins such as IL-1β or Gasdermin D that controls pyroptosis. There are multiple proteins working together in the immune cell to form inflammasomes, and different protein combinations can give different outcomes. Overactive inflammasomes have been implicated in several autoimmune diseases, several of which are associated with HS as comorbidities (more than one condition in the same person at once). We wish to build upon the existing limited knowledge of inflammasome activity in the skin and blood of HS patients to better understand how these complexes control IL-1b release and inflammatory cell death in this disease. To do this, we will use multiple molecular and cellular biology techniques to understand which inflammasomes are activated in HS and if they have a lower activation threshold compared to healthy donor samples. By gaining a fuller understanding of the biology of these inflammatory processes, we hope to uncover the underlying causes of HS and its chronicity. This may uncover targets for new therapies which are much needed for HS patients. The generosity of British Skin Foundation donors has given Daniel, Des and Brian the scope to take on this ambitious project which they hope will lead to a breakthrough in the understanding and treatment of an oft-neglected disease. Dr Daniel Johnston, University College Dublin Donate Read Beth's HS story HS information By donating to skin disease research, you are helping us to find treatments and cures for conditions like hidradenitis suppurativa, acne and psoriasis through to potential killers like melanoma skin cancer. Thank you.