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<p>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 <i>Ccl11</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Jaechan Ryu,
  • Amy Blondeau,
  • Olivier Mirabeau,
  • Selene Di Carlo,
  • Victoire Baillet,
  • David Hardy,
  • Christian Pasquali,
  • Lucie Peduto,
  • Gérard Eberl

摘要

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.