Fukuda-Ohta, Y. | Search bioRxiv

bioRxiv2023

A stress sensor IRE1α is required for bacterial exotoxin-induced inflammasome activation in tissue-resident macrophages

Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1{beta} (IL-1{beta}), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarified the roles of IRE1, an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1{beta} production from RPMs. In RPMs, CTB is incorporated into ER and induced ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1-deficient RPMs showed a significant impairment of CT- or CTB-induced IL-1{beta} production, indicating that IRE1 was required for CT- or CTB-induced IL-1{beta} production from RPMs. This study first demonstrates the critical roles of IRE1 in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages. One sentence summaryIRE1 is required for NLRP3 and pyrin-mediated IL-1{beta} production

immunology↗

bioRxiv2023

Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhi hepatic macrophages

Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhi hepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clo macrophages activated the transcription factors LXR and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently, Rnaset2-/- mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses in Rnaset2-/- mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages in Rnaset2-/- mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/540294v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@69614eorg.highwire.dtl.DTLVardef@737c69org.highwire.dtl.DTLVardef@1ecd9eforg.highwire.dtl.DTLVardef@d7e10d_HPS_FORMAT_FIGEXP M_FIG In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine. C_FIG

immunology↗