Trpm4 ion channels in pre-Bötzinger complex interneurons are essential for breathing motor pattern but not rhythm.

Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca2+)-activated nonselective cationic current (ICAN) to generate robust neural bursts. Hypothesized to be rhythmogenic, reducing ICAN is predicted to slow down or stop breathing; its contributions to motor pattern would be reflected in the magnitude of movements (output). We tested the role(s) of ICAN using reverse genetic techniques to diminish its putative ion channels Trpm4 or Trpc3 in preBötC neurons in vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased the tidal volume of breaths yet surprisingly increased breathing frequency, often followed by gasping and fatal respiratory failure. Mice transduced with Trpc3-targeted shRNA survived with no changes in breathing. Patch-clamp and field recordings from the preBötC in mouse slices also showed an increase in the frequency and a decrease in the magnitude of preBötC neural bursts in the presence of Trpm4 antagonist 9-phenanthrol, whereas the Trpc3 antagonist pyrazole-3 (pyr-3) showed inconsistent effects on magnitude and no effect on frequency. These data suggest that Trpm4 mediates ICAN, whose influence on frequency contradicts a direct role in rhythm generation. We conclude that Trpm4-mediated ICAN is indispensable for motor output but not the rhythmogenic core mechanism of the breathing central pattern generator.

IL-4 Inhibits the Biogenesis of an Epigenetically Suppressive PIWI-Interacting RNA To Upregulate CD1a Molecules on Monocytes/Dendritic Cells.

The discovery of PIWI-interacting RNAs (piRNAs) revealed the complexity of the RNA world. Although piRNAs were first deemed to be germline specific, substantial evidence shows their various roles in somatic cells; however, their function in highly differentiated immune cells remains elusive. In this study, by initially screening with a small RNA deep-sequencing analysis, we found that a piRNA, tRNA-Glu-derived piRNA [td-piR(Glu)], was expressed much more abundantly in human monocytes than in dendritic cells. By regulating the polymerase III activity, IL-4 potently decreased the biogenesis of tRNA-Glu and, subsequently, td-piR(Glu). Further, we revealed that the td-piR(Glu)/PIWIL4 complex recruited SETDB1, SUV39H1, and heterochromatin protein 1ß to the CD1A promoter region and facilitated H3K9 methylation. As a result, the transcription of CD1A was significantly inhibited. Collectively, we demonstrated that a piRNA acted as the signal molecule for a cytokine to regulate the expression of an important membrane protein for lipid Ag presentation.