This open access paper is not so easy to summarize. It is a tour of some of the details by which immune system aging provokes chronic inflammation and fibrosis, the harmful deposition of scar-like structures rather than successful tissue maintenance. All of the mentioned details interact with one another, and all of the mentioned details matter. The primary focus of the authors is the liver, an organ in which inflammation and fibrosis play significant and well-studied roles in aging and disease, but the discussion is applicable more broadly. The lesson to take from this is that rejuvenation of the aged immune system is an important goal, given the negative impact it has throughout the body.
Almost all mature cells that undergo apoptosis in an age-dependent or an accidental manner are completely recovered in tissue-specific microenvironments without any physiological changes. After peripheral blood leukocytes are released into the local region, fibroblast cells and new blood vessels commonly proliferate during wound healing. Inducible repair tools mainly supplied from blood vessels are cleared by peripheral blood phagocytic macrophages. Finally, hematopoietic stem cell (HSC)-derived precursor cells migrate from bone marrow (BM) to the microenvironment to rebuild damaged tissues.
In this review, we question how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH. We now propose the alternative inflammation and fibrosis pathway in CD40+ endothelial cells in hepatic sinusoids (HSECs) other than the main fibrosis pathway in HSCs. We suggest that HSCs are activated by bone marrow derived macrophages following the cell-cell interaction between senescent hepatocytes and senescent HSECs. However, the physiological condition of HSCs in a NASH-specific environment with chronic inflammation is still unclear. Therefore, it is very difficult to obtain a direct strategy for treating HSCs. Conversely, we hypothesized that senescent CD40+ HSECs are activated by CD154 on infiltrating senescent Th2 cells. This activation is enhanced by the cell-cell interaction among senescent hepatocytes, senescent HSECs, and senescent Küpffer cells.
Recently, the removal of senescent cells (senolysis) has been proposed for the treatment of lifestyle-related diseases. Kidney-type glutaminase (KGA) expression is increased according to low pH by lysosomal membrane damage. This induces an enhancement of the glutaminase 1 (GLS1) gene to maintain senescent cells. Senolysis induced by a GLS1 inhibitor rescues inflammation in lifestyle-related diseases. Therefore, we propose an alternative fibrosis pathway involving the cell-cell interaction of senescent cells in a NASH-specific environment with chronic inflammation at old age. Further examination is needed to determine how to control inflammation and fibrosis in older patients with lifestyle-related diseases, including NASH.