AUTHOR=Manzanares-Meza Laura D. , Gutiérrez-Román Claudia I. , Jiménez-Pineda Albertana , Castro-Martínez Felipe , Patiño-López Genaro , Rodríguez-Arellano Eunice , Valle-Rios Ricardo , Ortíz-Navarrete Vianney F. , Medina-Contreras Oscar TITLE=IL-36γ is secreted through an unconventional pathway using the Gasdermin D and P2X7R membrane pores JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.979749 DOI=10.3389/fimmu.2022.979749 ISSN=1664-3224 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.