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

Front Immunol. 2022 Aug 18:13:979749. doi: 10.3389/fimmu.2022.979749. eCollection 2022.

Abstract

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.

Keywords: IL-36γ; cytokin receptors; inflammation; macrophages; secretion.

MeSH terms

  • Animals
  • Biological Transport
  • Cytokines / metabolism
  • Immunity, Mucosal*
  • Interleukin-1
  • Mice
  • Phosphate-Binding Proteins / metabolism*
  • Pore Forming Cytotoxic Proteins / metabolism*
  • Receptors, Purinergic P2X7 / metabolism*

Substances

  • Cytokines
  • Gsdmd protein, mouse
  • IL1F9 protein, mouse
  • Interleukin-1
  • P2rx7 protein, mouse
  • Phosphate-Binding Proteins
  • Pore Forming Cytotoxic Proteins
  • Receptors, Purinergic P2X7