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Prostatic Escherichia coli Infection Drives CCR2-Dependent Recruitment of Fibrocytes and Collagen Production

Scharpf et al., Disease Models & Mechanisms. 2025.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11789281

In men, lower urinary tract dysfunction (LUTD) is commonly linked to prostatic collagen accumulation through inflammation-mediated mechanisms. Researchers used 8- to 10-week-old male reporter mice, exposed to either sterile phosphate buffered saline (PBS) or Escherichia coli, to identify that circulating Lyz2+S100a4+Gli1+ myeloid-derived cells are recruited to the prostate to drive inflammation and collagen synthesis. Researchers also used 8- to 10-week-old male Ccr2‑/ - null and Ccr2+/- control mice, exposed to either sterile PBS or E. coli, to determine if Ccr2 is necessary for the fibrotic response to prostatic uropathogen infection. Results demonstrated that CCR2+ cells mediate the collagen abundance and fibrotic response to prostate inflammation. This study elucidates the cell types underlying prostate fibrosis and can be utilized to develop targeted therapies. Supported by ORIP (T32OD010957), NCI, NIDDK, and NIEHS.

A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis

Peters et al., Science Translational Medicine. 2023.

https://www.science.org/doi/10.1126/scitranslmed.abn7491

Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.

Fructose Stimulated De Novo Lipogenesis Is Promoted by Inflammation

Jelena  et al., Nature Metabolism. 2020.

https://pubmed.ncbi.nlm.nih.gov/32839596

Non-alcoholic fatty liver disease (NAFD) affects 30% of adult Americans. While NAFD starts as simple steatosis with little liver damage, its severe manifestation as non-alcoholic steatohepatitis (NASH) is a leading cause of liver failure, cirrhosis, and cancer. Fructose consumption is proposed to increase the risk of hepatosteatosis and NASH. Excessive intake of fructose causes barrier deterioration and low-grade endotoxemia. Using a mouse model, the study examined the mechanism of how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis. The results demonstrated that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to fatty acid in both mouse and human hepatocytes. The finding may be of relevance to several common liver diseases and metabolic disorders. Supported by ORIP (S10OD020025), NCI, NIEHS, NIDDK, NIAID, and NIAAA.