Long-term inhibition of protease hypersensitivity by initial immunological cross-regulation and epigenetic memory in lung stromal cells

Prevention and regulation of excessive inflammation is a key target to protect against inflammatory pathologies such as autoimmunity and allergy. In a mouse model of acute lung protease hypersensitivity, we assessed the efficacy of immunological cross-regulation to mitigate pathogenic inflammation. We show that induction of a type 1 response using Toll-like receptor ligands or a bacterial lysate efficiently blocks acute eosinophilia and type 2 responses evoked by the cysteine protease papain. Upon rechallenge with papain weeks later, mice displayed enhanced type 2 responses and eosinophilia, whereas this response was absent if the initial inflammation was cross-regulated. Memory of the initial event was stored in adventitial stromal cells expressing CCL11. Accessibility of the Ccl11 locus was increased by papain exposure in an interleukin-4- and interleukin-13-dependent manner and blocked by interferon gamma. Our results show how the nature of an initial inflammation is memorized by tissue-resident cells and shapes subsequent inflammatory responses.