Enzyme-regulating macrophages present in each people and mice open the door to translating findings in mice into human therapies. Credit: Issey Takahashi
According to a examine printed in Cell Death & Disease, scientists at Nagoya University in Japan have found two enzymes that play a task in macrophage polarization, a key issue affecting fibrosis. The findings of the examine counsel a promising therapy risk for human sufferers.
Kidney fibrosis is a lethal inflammatory illness that leads to the stiffening and lack of regular operate of the kidneys. The illness is related to a mechanism referred to as macrophage polarization. Macrophages, that are white blood cells that help the physique in combating infections and repairing tissues, endure polarization in response to adjustments of their microenvironment. This polarization leads to two several types of macrophages: M1, which causes irritation, and M2, which possesses anti-inflammatory and tissue restore capabilities.
Because macrophage polarization is tightly managed and includes a number of signaling pathways and regulatory networks, imbalances on this course of are widespread in lots of inflammatory ailments. In sufferers with kidney fibrosis, there may be an imbalance between M1 and M2 macrophages. In this example, M2 macrophages, which usually suppress irritation, proliferate excessively and secrete elements that promote fibrosis.
Although these imbalances could also be therapeutic targets, that is hampered by the truth that the mechanism of macrophage polarization concerned in kidney fibrosis continues to be poorly understood. Furthermore, the molecular mechanisms of macrophage polarization have little in widespread between mice and people, making it tough to translate analysis outcomes obtained in mice to human ailments.
A Nagoya University research group led by Assistant Professor Hideki Tatsukawa, graduate student Yoshiki Shinoda, and Professor Hitomi Kiyotaka of the Graduate School of Pharmaceutical Sciences, in collaboration with Professor Takayoshi Suganami and Lecturer Miyako Tanaka of the Research Institute of Environmental Medicine, has identified an enzyme associated with kidney fibrosis in both mice and human models called protein cross-linking enzyme transglutaminase (TG2). Their discovery opens the possibility of translating findings in mouse models into therapies for human patients.
As its name suggests, TG2 is involved in the cross-linking of amino acid residues in proteins. In fibrosis models, TG2 induces another enzyme, arachidonic acid oxidase (ALOX15), through the cross-linking process. Since previous studies have reported that ALOX15 is involved in M2 macrophage induction, the group’s findings suggest that TG2 activity exacerbates kidney fibrosis by polarizing M2 macrophages using ALOX15.
“Macrophage polarization, which promotes fibrosis through cross-linking enzymes, has a similar induction mechanism in both humans and mice,” Tatsukawa said. “By targeting the regulation of macrophage function, we hope to develop treatments for various diseases caused by an imbalance between the promotion and suppression of inflammation, such as fibrosis, cancer, and atherosclerosis.”
Their research also suggests that drugs developed for celiac disease, that inhibit TG2, could be repurposed to treat fibrosis. “TG2 also converts wheat gluten into gliadin, which is known to cause gluten sensitivity (celiac disease),” Tatsukawa said. “A TG2 inhibitor has been developed for the treatment of this celiac disease and is currently in clinical trials. We believe that this inhibitor could be used in the treatment of fibrosis because researchers, including our group, have found that the administration of TG2 inhibitors suppresses the pathogenesis of fibrosis models in the kidney, liver, and lung.”
Reference: “Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages” by Yoshiki Shinoda, Hideki Tatsukawa, Atsushi Yonaga, Ryosuke Wakita, Taishu Takeuchi, Tokuji Tsuji, Miyako Tanaka, Takayoshi Suganami and Kiyotaka Hitomi, 2 March 2023, Cell Death & Disease.
DOI: 10.1038/s41419-023-05622-5
