Kyoto University finds that macrophages promote granuloma formation in the body — Regulation of the pentose phosphate pathway is key for treatment

When foreign bodies and pathogens enter the body, the immune system is responsible for eliminating them. If this cannot be achieved, granulomas are formed to contain them. In diseases where these form, such as sarcoidosis, granulomas are formed even in the absence of foreign bodies in the body. Granulomas in the eye may cause vision loss and those in the heart may result in arrhythmia or sudden death; however, only symptomatic therapy is available because the disease causes are unknown.

A research group led by Professor Kenji Kabashima of the Department of Dermatology at the Graduate School of Medicine at Kyoto University, and Program-Specific Junior Associate Professor Lecturer Satoshi Nakamizo at the Alliance Laboratory for Advanced Medical Research, and Department of Dermatology at Kyoto University Graduate School of Medicine examined sarcoidosis granuloma cells and discovered that high expression of the enzyme fructose-1,6-bisphosphatase 1 (FBP1) results in the upregulation of the pentose phosphate pathway and macrophage-promoting granuloma formation. Nakamizo stated, "Since similar results have been obtained for other granulomatous diseases, we believe that the mechanism found in our study is a common mechanism in granulomas. We are currently working on developing therapeutics for practical applications in collaboration with a pharmaceutical company that possesses an FBP1 inhibitor library." The study results were published online in the Journal of Clinical Investigation.

Using the single-cell ribonucleic acid (RNA) sequencing technique, the research group performed a comprehensive analysis of skin cells from healthy individuals and immune cells in skin lesions from patients with sarcoidosis. They found that the percentage of macrophages that express triggering receptor expressed on myeloid cells 2 (TREM2) was increased in the immune cells from the patients. These TREM2-positive macrophages expressed elevated levels of FBP1, a glycolysis-related enzyme.

FBP1 expression was also elevated in the granulomas in the lungs, heart, and lymph nodes and the blood concentration of FBP1 was elevated in patients with sarcoidosis. FBP1 enhances immune attack by activating the pentose phosphate pathway to generate acid during the adenosine triphosphate production pathway. The pentose phosphate pathway was also upregulated in granuloma cells from patients.

The research group confirmed that treating human monocyte-derived granuloma cells with pentose phosphate pathway inhibitors attenuates granulomatous mass formation. Attenuation of granuloma formation was also observed in murine granuloma models treated with either an FBP1 or a pentose phosphate pathway inhibitor.

FBP1 inhibitors are currently under development for the treatment of diabetes and some of the compounds are being assessed in clinical trials. The research group has filed a patent application based on the study results and is pursuing clinical application in collaboration with a major domestic pharmaceutical company.