Frontiers in Immunology (Aug 2022)

IL-36γ is secreted through an unconventional pathway using the Gasdermin D and P2X7R membrane pores

  • Laura D. Manzanares-Meza,
  • Laura D. Manzanares-Meza,
  • Claudia I. Gutiérrez-Román,
  • Albertana Jiménez-Pineda,
  • Felipe Castro-Martínez,
  • Genaro Patiño-López,
  • Eunice Rodríguez-Arellano,
  • Ricardo Valle-Rios,
  • Ricardo Valle-Rios,
  • Vianney F. Ortíz-Navarrete,
  • Oscar Medina-Contreras

DOI
https://doi.org/10.3389/fimmu.2022.979749
Journal volume & issue
Vol. 13

Abstract

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Mucosal innate immunity functions as the first line of defense against invading pathogens. Members of the IL-1 family are key cytokines upregulated in the inflamed mucosa. Inflammatory 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-36γ accumulation within the cell. In silico modeling indicates IL-36γ can pass through both the P2X7R and Gasdermin D pores, and both IL-36γ, P2X7R and Gasdermin D mRNA are upregulated in inflammation; further, experimental blockade of these receptors’ limits IL-36γ release. Our results demonstrate that IL-36γ is secreted mainly by an unconventional pathway through membrane pores formed by P2X7R and Gasdermin D.

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