Modulation of circulating cytokine production in alcoholic patients infected with Strongyloides stercoralis.

Strongyloidiasis control is associated with a Th2 immune response. However, alcohol ingestion plays an important role in modulating the immune system. The aim of this study is to evaluate the occurrence of Strongyloides stercoralis infection in alcoholic patients, the levels of circulating cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-15 and IL-17), and its correlation with modulation of parasitic load in alcoholic individuals infected with S. stercoralis. A total of 336 alcoholic patients, treated at the Alcoholic Care and Treatment Center were included in this study. The cytokine levels were measured by a commercial ELISA in 80 sera divided into four groups with 20 individuals each: alcoholics infected (ASs+) and not infected (ASs-) with S. stercoralis and non-alcoholics infected (NASs+) and not infected (NASs-) with the helminth. S. stercoralis frequency in alcoholic patients was 16.1% (54/336). The parasitic load varied from 1 to 546 larvae/g of faeces, median and interquartile range (IQR) of 9 and 1.0-62.5 larvae/g of faeces, while in non-alcoholic individuals the parasitic load was less than 10 larvae/g of faeces. Levels of circulating IL-4 were significantly higher in ASs+ when compared with NASs- group (p < .05). An inverse correlation between serum levels of IFN-γ and parasitic load in alcoholic patients infected with S. stercoralis was observed (r = -601; p < 0.01). These results suggest that modulation of IFN-γ production occurs in alcoholic individuals with high parasitic burden.

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.