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

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.

[Diagnostic criteria for hypoalphalipoproteinemia and the threshold associated with cardiovascular protection in a Mexican Mestizo population]. / Criterio diagnóstico para hipoalfalipoproteinemia y punto de corte asociado con protección cardiovascular en una población mestiza mexicana.

BACKGROUND AND OBJECTIVES: In the Mexican Mestizo and Indian populations it is unknown the diagnostic criteria (DC) and associated risk of myocardial infarction (MI) for the HDL-cholesterol (HDL-c). We aimed to establish, in a Mexican adult population without cardiovascular risk factors, their HDL-c concentrations, the DC for hypoalphalipoproteinemia and prevalence base on the percentile-10 and the risk associated with MI, as well as the threshold (TH) associated with cardiovascular protection. SUBJECTS AND METHODS: In 826 adult Mestizos, 98 Indians and 155 Mestizos with MI for the first time the average HDL-c serum concentrations were determined. Then the percentile and statistical analysis were carried out. RESULTS: The average HDL-c (mg/dl) concentrations for Mestizos and Indians were 43.2 and 37.2 and the ones inferior to the percentile-10 were <30 and <26, respectively. In Mestizos, HDL-c concentrations of ≤ 35 mg/dl (odds ratio [OR] 1.91, 95% confidence interval [95%CI] 1.3-2.8, P=.001) were associated with MI and those >35 (OR 0.52, IC 95% 0.36-0.76, P=.001) were associated with a cardiovascular protection of 52%. The hypoalphalipoproteinemia prevalences in Mestizos and Indians were: for the percentile-10 DC 9 and 11% and for the TH associated with MI ≤ 35, 26 and 54%, respectively. CONCLUSIONS: The Indians average HDL-c concentration was significantly lower (P<.003) than for Mestizos. The established DC showed that the hypoalphalipoproteinemia prevalences in both populations were similar to those for other open populations. In Mestizos, HDL-c concentrations > 35 mg/dl are protective for MI, but it will be necessary to establish this TH for the Indian population. Each population should establish its own DC for hypoalphalipoproteinemia.