Autoimmune susceptibility gene PTPN2 is required for clearance of adherent-invasive Escherichia coli by integrating bacterial uptake and lysosomal defence

Abstract

ObjectivesAlterations in the intestinal microbiota are linked with a wide range of autoimmune and inflammatory conditions, including inflammatory bowel diseases (IBD), where pathobionts penetrate the intestinal barrier and promote inflammatory reactions. In patients with IBD, the ability of intestinal macrophages to efficiently clear invading pathogens is compromised resulting in increased bacterial translocation and excessive immune reactions. Here, we investigated how an IBD-associated loss-of-function variant in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene, or loss of PTPN2 expression affected the ability of macrophages to respond to invading bacteria.DesignIBD patient-derived macrophages with wild-type (WT) PTPN2 or carrying the IBD-associated PTPN2 SNP, peritoneal macrophages from WT and constitutive PTPN2-knockout mice, as well as mice specifically lacking PTPN2 in macrophages were infected with non-invasive K12 Escherichia coli, the human adherent-invasive E. coli (AIEC) LF82, or a novel mouse AIEC (mAIEC) strain.ResultsLoss of PTPN2 severely compromises the ability of macrophages to clear invading bacteria. Specifically, loss of functional PTPN2 promoted pathobiont invasion/uptake into macrophages and intracellular survival/proliferation by three distinct mechanisms: Increased bacterial uptake was mediated by enhanced expression of carcinoembryonic antigen cellular adhesion molecule (CEACAM)1 and CEACAM6 in PTPN2-deficient cells, while reduced bacterial clearance resulted from defects in autophagy coupled with compromised lysosomal acidification. In vivo, mice lacking PTPN2 in macrophages were more susceptible to mAIEC infection and mAIEC-induced disease.ConclusionsOur findings reveal a tripartite regulatory mechanism by which PTPN2 preserves macrophage antibacterial function, thus crucially contributing to host defence against invading bacteria.

Interaction Between Commensal Bacteria, Immune Response and the Intestinal Barrier in Inflammatory Bowel Disease

“…For patients with IBD who lack PTPN2 (an autoimmune susceptibility gene) or mutations in PTPN2 , this is more like a help. Macrophages won’t against AIEC ( 67 ). At the same time as the increase in pathogenic bacteria, the proportion of beneficial commensal bacteria such as Firmicutes , Clostridiales , Bacteroides , Ruminococcaceae, Lactobacillus , Bifidobacteria , Faecalibacterium prausnitzii and other butyrate- producing bacteria in the intestine is significantly reduced, which is also an important factor in the development of IBD ( 53 , 54 , 68 ).…”

Interactions of pathogenic Escherichia coli with CEACAMs

“…Indeed, the pathogenesis of inflammatory bowel disease is complex, potentially involving not only AIEC, but human susceptibility genes including a loss of function variant of the protein tyrosine phosphatase non-receptor type 2 ( PTPN2 ) gene ( 34 ). Notably, PTPN2 appears to modulate the gut microbiome ( 35 ) and loss of PTPN2 is associated with enhanced CEACAM expression and enhanced AIEC uptake and intracellular survival ( 36 ), suggesting that Crohn’s disease may reflect the interplay of pathogenic E. coli and distinctly susceptible hosts.…”

Scutellaria baicalensis georgi is a promising candidate for the treatment of autoimmune diseases

“…Comprised with ulcerative colitis and Crohn's disease, inflammatory bowel disease (IBD) is characterized as intestinal microbiota alterations which are linked with a wide range of autoimmune conditions (Spalinger et al, 2022). A recent released review concentrated on the up-to-date studies investigating the affection of baicalin on IBD, indicating BAI can be a promising therapeutic prospect as a potential supplementary agent due to it reversed IBD by virtue of anti-inflammation and antioxidant properties, immune regulation, as well as maintenance of intestinal barrier and intestinal flora balance (Wang X. et al, 2022).…”