Enzyme-regulating macrophages found in both mice and people unlock to translating findings in mice into human therapies. Credit: Issey Takahashi
According to a research study released in Cell Death & & Disease, scientists at Nagoya University in Japan have discovered 2 enzymes that contribute in macrophage polarization, a crucial element impacting fibrosis. The findings of the research study suggest a promising treatment possibility for human patients.
Kidney fibrosis is a lethal inflammatory illness that leads to the stiffening and loss of regular function of the kidneys. The disease is associated with a system referred to as macrophage polarization. Macrophages, which are leukocyte that assist the body in battling infections and fixing tissues, undergo polarization in response to changes in their microenvironment. This polarization results in two various types of macrophages: M1, which triggers swelling, and M2, which has anti-inflammatory and tissue repair work abilities.
Because macrophage polarization is tightly controlled and involves multiple signaling pathways and regulative networks, imbalances in this procedure prevail in numerous inflammatory diseases. In clients with kidney fibrosis, there is an imbalance in between M1 and M2 macrophages. In this situation, M2 macrophages, which generally suppress inflammation, proliferate excessively and produce elements that promote fibrosis.
These imbalances might be therapeutic targets, this is hampered by the fact that the system of macrophage polarization involved in kidney fibrosis is still improperly understood. In addition, the molecular mechanisms of macrophage polarization have little in typical between humans and mice, making it challenging to equate research results obtained in mice to human illness.
A Nagoya University research study group led by Assistant Professor Hideki Tatsukawa, graduate student Yoshiki Shinoda, and Professor Hitomi Kiyotaka of the Graduate School of Pharmaceutical Sciences, in partnership with Professor Takayoshi Suganami and Lecturer Miyako Tanaka of the Research Institute of Environmental Medicine, has actually identified an enzyme connected with kidney fibrosis in both mice and human designs called protein cross-linking enzyme transglutaminase (TG2). Their discovery opens the possibility of translating findings in mouse designs into therapies for human patients.
As its name recommends, TG2 is associated with the cross-linking of amino acid residues in proteins. In fibrosis designs, TG2 causes another enzyme, arachidonic acid oxidase (ALOX15), through the cross-linking procedure. Since previous studies have reported that ALOX15 is included in M2 macrophage induction, the groups findings suggest that TG2 activity worsens kidney fibrosis by polarizing M2 macrophages utilizing ALOX15.
” Macrophage polarization, which promotes fibrosis through cross-linking enzymes, has a similar induction system in both mice and human beings,” Tatsukawa said. “By targeting the policy of macrophage function, we want to develop treatments for various diseases brought on by an imbalance between the promotion and suppression of swelling, such as atherosclerosis, cancer, and fibrosis.”
Their research also recommends that drugs established for celiac disease, that hinder TG2, might be repurposed to treat fibrosis. We think that this inhibitor could be utilized in the treatment of fibrosis because researchers, including our group, have found that the administration of TG2 inhibitors reduces the pathogenesis of fibrosis models in the liver, lung, and kidney.”
Recommendation: “Tissue transglutaminase worsens kidney fibrosis through 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.
Because macrophage polarization is securely controlled and includes multiple signaling paths and regulative networks, imbalances in this procedure are typical in numerous inflammatory diseases. In patients with kidney fibrosis, there is an imbalance between M1 and M2 macrophages. In this situation, M2 macrophages, which generally reduce inflammation, multiply exceedingly and produce aspects that promote fibrosis.
Given that previous research studies have reported that ALOX15 is included in M2 macrophage induction, the groups findings suggest that TG2 activity intensifies kidney fibrosis by polarizing M2 macrophages utilizing ALOX15.
