MEFV and NLRP3 Inflammasome Expression Is Attributed to Immature Macrophages and Correlates with Serum Inflammatory Proteins in Crohn´s Disease Patients

• Published in: Inflammation 2022-08, Vol.45 (4), p.1631-1650
• Main Authors: Gorreja, Frida, Caër, Charles, Rush, Stephen T. A., Forsskål, Sophia K., Härtlova, Anetta, Magnusson, Maria K., Bexe Lindskog, Elinor, Börjesson, Lars G., Block, Mattias, Wick, Mary Jo
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedical Laboratory Science/Technology; Biomedicine; Biomedicinsk laboratorievetenskap/teknologi; Blood Proteins - metabolism; Cell and Molecular Biology; Cell Biology; Cell- och molekylärbiologi; cells; colitis; Crohn Disease - metabolism; Epithelial cells; epithelium; Flow cytometry; Gastroenterologi; Gastroenterology and Hepatology; Gene expression; Humans; IL-1β; IL-6; Ileum; Immunologi inom det medicinska området; Immunology; Immunology in the medical area; Infectious Medicine; Infektionsmedicin; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interleukin-1beta - metabolism; Internal Medicine; intestinal inflammation; Intestine; Kinases; Lamina propria; Macrophages; Macrophages - metabolism; Medical Genetics; Medicinsk genetik; Monocytes; Mucosa; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRPs; Original; Original Article; Pathology; Pharmacology/Toxicology; Proteins; Pyrin - genetics; Pyrin - metabolism; responses; Rheumatology; TRAIL
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-022-01647-8

Inflammasomes are intracellular protein complexes whose activation results in proinflammatory cytokines. Inflammasomes are implicated in Crohn´s disease (CD) pathogenesis, yet the contribution of inflammasomes in intestinal epithelial cells (IECs) versus lamina propria (LP) macrophages is poorly understood. Whether inflammasome expression in intestinal tissue reflects the serum inflammatory protein profile of patients is also not known. We aimed to determine the intestinal cell types where inflammasome expression is increased in CD and if they correlate with the serum protein profile. RT-PCR and NanoString nCounter technology were used to characterize inflammasome gene expression in CD patients and controls. The mucosa, LP and IEC cell fractions and FACS-sorted cells were analyzed. Proximity extension assay with a 92-protein panel was used to determine the serum inflammatory protein profile. Compositional analysis was used to correlate ileum inflammasome gene expression with intestinal mononuclear phagocyte populations. We show that NLRP3 and MEFV inflammasome sensors and downstream effector expression including IL-1β are increased in inflamed mucosa of IBD patients and correlate with disease activity. Inflammasome gene expression increased with the abundance of immature intestinal macrophages, and increased IL-1β released by CD LP cells correlated with immature macrophage frequency. Inflammasome gene expression was also increased in circulating monocytes, the precursors of immature intestinal macrophages. Finally, the serum inflammatory profile of CD patients correlates with ileal expression of genes related to NLRP3 and MEFV inflammasomes. Overall, we show that MEFV and NLRP3 inflammasome expression in CD intestine is attributed to the accumulation of immature macrophages and correlates with serum inflammatory proteins.