Identification and characterization of the mechanisms and relevance of inflammasome activation in mast cells

• Applicant: Professor Dr. Marcus Maurer (†)
• Subject Area: Dermatology ; Immunology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255956848

Traditionally, mast cells (MCs) are seen mainly as effector cells of the adaptive immune system, since they can mediate anaphylactic reactions upon allergen-induced IgE crosslinking. However, MCs are emerging as key contributors to innate immune responses: They express a large repertoire of innate immune signaling receptors, including most members of the Toll-like receptor (TLR) family, Rig-I like receptors and Nod-like receptors. Similar to macrophages and dendritic cells, MCs can be activated by danger signals derived from pathogens, and they can sense altered host molecules that appear during tissue damage. Inflammasomes are an important class of innate immunity sensors for such danger signals. Via Interleukin 1 beta (IL-1 beta), they drive early inflammatory responses during tissue damage by sensing many endogenous molecules that are altered by cell stress or mislocalized during bacterial infection. Many prevalent diseases in Western societies, including chronic obstructive pulmonary disease, metabolic syndrome, atherosclerosis and Alzheimer disease are influenced by erroneous activation of inflammasomes such as NLRP3, which is now considered a promising therapeutic target. Recent studies have highlighted the importance of MC inflammasome activation for the development of skin lesions in patients with autoinflammatory conditions. The importance of MC inflammasome activation beyond these conditions has so far not been studied. Chronic wounds, complicated by bacterial superinfection, present an increasing medical and economic burden with an incidence of 2% in aging Western societies. Chronic wound infections are associated with increased activation of mast cells and inflammasome mediators such as IL-1 beta. UV-irradiation is a sterile inflammasome activator and causes MC-mediated inflammation that is linked to the development of melanoma. We are, therefore, interested in studying the connection between MCs and inflammasome activation in these two conditions. Our preliminary data show that human and mouse MCs express a wide range of functional inflammasomes and that they respond towards inflammasome stimuli independently of histamine release. We, here, propose to study the pathways of inflammasome activation in MC-dependent models of inflammation with the help of an inflammasome reporter mouse (m-ASC-cerulean). Secondly, we will reconstitute MC-deficient mice selectively with MCs that lack different inflammasomes to identify the role of specific inflammasomes in disease development. We will then assess the relevance of MC inflammasome activation in human skin inflammation. Finally, as a proof of principle, we will test the effect of small molecules identified by high throughput screens as inflammasome activation mosulators on MCs. We thereby aim to swiftly translate our findings and generate new therapeutic perspectives for MC- and inflammasome-related skin diseases.

• DFG Programme: Research Grants
• Participating Persons: Professor Dr.-Ing. Jürgen Lademann; Professor Dr. Eicke Latz