Role of IL-36 cytokines in the regulation of the immune response in intestinal mucosa
Mucosal innate immunity functions as the rst line of defense against invading pathogens. Members of the IL-1 family are key cytokines upregulated in the in amed mucosa. In ammatory cytokines are regulated by limiting their function and availability through their activation and secretion mechanisms. IL-1 cytokines secretion is affected by the lack of a signal peptide on their sequence, which prevents them from accessing the conventional protein secretion pathway; thus, they use unconventional protein secretion pathways. Here we show in mouse macrophages that LPS/ATP stimulation induces cytokine relocalization to the plasma membrane, and conventional secretion blockade using monensin or Brefeldin A triggers no IL-36\(\gamma\) accumulation within the cell. In silico modeling indicates IL-36\(\gamma\) can pass through both the P2X7R and Gasdermin D pores, and both IL-36\(\gamma\), P2X7R and Gasdermin D mRNA are upregulated in in ammation; further, experimental blockade of these receptors’ limits IL-36\(\gamma\) release. Our results demonstrate that IL-36\(\gamma\) is secreted mainly by an unconventional pathway through membrane pores formed by P2X7R and Gasdermin D.
This research axis was conceived as an open and evolving space for the role of IL-36 in intestinal inflammation.
Project Outputs
A first paper, published in J Interferon Cytokine Res (manzanares2022?) explores the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source.
See also David L Woodland’s related comment in a blog post on EurekAlert!: https://www.eurekalert.org/news-releases/944598
A second paper was published in Frontiers in Immunology (manzanares2022?). It shows in mouse macrophages that LPS/ATP stimulation induces cytokine relocalization to the plasma membrane, and conventional secretion blockade using monensin or Brefeldin A triggers no IL-36γ accumulation within the cell, demonstrating that IL-36γ is secreted mainly by an unconventional pathway through membrane pores formed by P2X7R and Gasdermin D..
This work also inspired a spin-off project on the metabolic role of IL-36.