Intestinal edema induced by LPS-induced endotoxemia is associated with an inflammasome adaptor ASC

• Published in: PloS one Vol. 18; no. 2; p. e0281746
• Main Authors: Yamamoto, Toshihiro, Kurata, Mie, Kaneko, Naoe, Masumoto, Junya
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.02.2023; Public Library of Science (PLoS)
• Subjects: Advertising executives; Alveoli; Analysis; Animal tissues; Animals; Apoptosis; Biology and Life Sciences; Bone marrow; Capillaries; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; Care and treatment; Caspase 1 - metabolism; Caspase-1; Cell-free system; Composition; Congestion; CRISPR; Diagnosis; Dropsy; Drug delivery; Drugs; Edema; Endotoxemia; Endotoxemia - chemically induced; Genes; Health aspects; Histopathology; Infiltration; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inflammation - metabolism; Interleukin-1beta - metabolism; Interleukins; Intestine; Kidneys; Lethal dose; Leukocytes (neutrophilic); Lipopolysaccharides; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; MicroRNAs; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Pathogens; Potassium; Proteins; Rank tests; Rankings; Research and Analysis Methods; Risk factors; Sepsis; Small intestine; Spleen; Statistical analysis; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0281746

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/caspase-1/interleukin(IL)-1β axis, also known as the inflammasome pathway, is indispensable for IL-1β activation in response to various pathogens or own damages. Previously, we developed an NLRP3-inflammasome using a cell-free system and identified ASC targeting drugs; thus, examination of ASC-related histopathology in various diseases could help to provide indications for these drugs. Here, we generated mice deficient only in ASC-protein (ASC-deficient (AD) mice) using CRISPR/Cas9 technology, studied which tissues were most affected, and obtained histopathological images of lipopolysaccharide (LPS)-induced endotoxemia. C57BL/6 wild-type (WT) and (AD) mice were injected intraperitoneally with a lethal dose (50 μg/g) of LPS. Statistical analysis of the survival of C57BL/6 mice and AD mice was performed using the Kaplan-Meier method and the log-rank test. The histopathological findings of multiple tissues from these mice were compared. Acute inflammation (e.g., catarrhal inflammation), along with congestion was observed in the colon of WT mice but not in that of AD mice. Adhesion of neutrophils to capillaries, along with interstitial infiltration, were observed in multiple tissues from WT mice. In AD mice, neutrophil infiltration was less severe but remained evident in the stomach, small intestine, heart, liver, kidney, spleen, and brain. Notably, there was no difference between WT and AD mice with respect to alveolar neutrophil infiltration and interstitial edema. These findings suggest that even though ASC contributes to systemic inflammation, it is dependent on the tissue involved. Intestinal congestion and edema might be good candidates for anti-ASC-targeted therapy.