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.

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

Fundamento y objetivos: En las poblaciones mestiza e indígena mexicanas se desconocen los criterios diagnósticos y el riesgo asociado a infarto de miocardio (IM) para el colesterol unido a lipoproteínas de alta densidad (colesterol HDL). El objetivo de este estudio fue establecer, en una población de adultos mexicanos sin factores de riesgo cardiovascular, las concentraciones de colesterol HDL, los criterios diagnósticos para hipoalfalipoproteinemia y prevalencia con base al percentil-10 y al riesgo asociado a IM, y el punto de corte asociado con protección cardiovascular.Sujetos y método: Se determinaron las concentraciones séricas de colesterol HDL promedio en 826 mestizos, 98 indígenas y 155 mestizos con IM de primera vez. Se realizaron los análisis de percentiles y estadísticos correspondientes. Resultados: Las concentraciones promedio de colesterol HDL en mestizos e indígenas fueron: 43,2 y 37,2mg/dl y las inferiores del percentil-10 <30 y <26mg/dl, respectivamente. En mestizos, las concentraciones de colesterol HDL ≤35mg/dl (odds ratio [OR] 1,91, intervalo de confianza del 95% [IC 95%] 1,3-2,8, p=0,001) se asociaron con IM y las >35mg/dl (OR 0,52, IC 95% 0,36-0,76, p=0,001) con una protección cardiovascular del 52%. Las prevalencias de hipoalfalipoproteinemia en mestizos e indígenas fueron para el criterio diagnóstico del percentil-10 del 9 y 11%, y para el asociado a IM del 26 y 54%, respectivamente. Conclusiones:La concentración promedio de colesterol HDL en indígenas fue significativamente menor (p<0,003) que en mestizos. Los criterios diagnósticos establecidos mostraron que las prevalencias de hipoalfalipoproteinemia en ambas poblaciones son similares a las de otras poblaciones abiertas. En mestizos, concentraciones de colesterol HDL>35mg/dl son protectoras para IM, pero será necesario establecer este punto de corte en población indígena. Cada población debe establecer sus criterios diagnósticos para hipoalfalipoproteinemia (AU)

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 methodsIn 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.ResultsThe 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 ≤35mg/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 >35mg/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 hypoalphalipoproteine mia (AU)

[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.