The main job of white blood cells is to drive inflammation and activate the immune system, but recent studies have shown that some white blood cells can actually help alleviate inflammation and promote healing.
Metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis, is an inflammatory condition marked by liver scarring or fibrosis, which gradually deteriorates liver function.
This disease significantly raises the risk of developing cirrhosis and liver cancer. Due to limited treatment options, MASH stands as the second most common reason for liver transplants in the U.S., following cirrhosis linked to chronic hepatitis C.
To develop effective therapies, it is crucial to gain insight into the underlying mechanisms that cause MASH. In a recent study published on August 19, 2024, in PNAS, researchers from Sanford Burnham Prebys, the University of California San Diego School of Medicine, and other institutions explored the intricate relationship between damaged liver cells and macrophages, which are a type of white blood cell involved in eliminating harmful cells and aiding normal healing processes.
Debanjan Dhar, PhD, an associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, leads this study. David Brenner, MD, CEO and president of Sanford Burnham Prebys, along with Christopher Glass, MD, PhD, a professor at UC San Diego, are credited as corresponding authors. The first author is Souradipta Ganguly, PhD, a postdoctoral researcher at both UC San Diego and Sanford Burnham Prebys.
The researchers discovered that the diverse types of macrophages involved in MASH vary based on whether the disease is worsening or improving. They identified specific macrophage subtypes that play a vital role in resolving MASH and liver fibrosis, where the buildup of scar tissue hampers the liver’s ability to function properly or heal itself. This fibrotic tissue obstructs blood flow, putting the entire organ at risk.
“In MASH, Kupffer cells (a specific kind of liver macrophage) are diminished and replaced by four unique macrophage subtypes. During regression of the disease—meaning symptoms and severity decrease—two subtypes of lipid-associated macrophages take the lead and express TREM2, a receptor that plays a role in cell survival, growth, and anti-inflammatory reactions,” explained Brenner.
“The presence of TREM2+ macrophages is essential for MASH regression. They not only halt the progression of MASH-related fibrosis but also effectively reduce inflammation. Without TREM2+ macrophages, the disease tends to progress.”
In its early and moderate stages, MASH often shows no clear symptoms, which contributes to its epidemic status in the U.S. The American Liver Foundation estimates that between 80 to 100 million Americans are affected by fatty liver disease, which can advance to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer, and ultimately death, particularly when accompanied by other issues like obesity.
It is estimated that 1.5% to 6.5% of adults in the U.S. have MASH, and about 24% of adults suffer from metabolic dysfunction-associated steatotic fatty liver disease, which is a precursor to MASH, cirrhosis, and other serious conditions.
“Our research indicates that lipid-associated macrophages expressing TREM2 are necessary for both the emergence of more lipid-associated macrophages and their healing functions,” said Dhar.
“The effective breakdown of scar tissue, which protects the liver, is driven by TREM2, and without TREM2+ macrophages, the liver struggles to eliminate fibrotic tissue, damaging the overall immune response and healing process.”
Looking ahead, the researchers suggest that a TREM2 agonist—a drug or substance that simulates TREM2’s effects—could prove useful in treating MASH/fibrosis and may help encourage regression for patients making lifestyle changes, losing weight, or undergoing bariatric surgery.
“Currently, there is only one approved treatment for MASH, which was only granted approval earlier this year,” stated Glass. “We must explore any possibilities to broaden treatment options for patients, as liver disease is worsening both in the U.S. and worldwide.”
Other contributors to the study included Sara Brin Rosenthal, Kei Ishizuka, Theresa V. Rohm, Naser Khader, Sebastiano Archilei, Jerrold M. Olefsky, Ariel E. Feldstein, Tatiana Kisseleva, and Rohit Loomba of UC San Diego; Ty D. Troutman from UC San Diego and Cincinnati Children’s Hospital Medical Center; as well as German Aleman Muench, Yasuyo Sano, and Pejman Soroosh from Janssen Research & Development in San Diego.
This study received financial support from the National Institutes of Health for D.D. (R01DK137061, R01DK133930), the Altman Clinical and Translational Research Institute (ACTRI — KL2TR001444), and the San Diego Digestive Diseases Research Center (NIH DK120515). Some support came from the ACTRI (NIH UL1TR001442). T.K. received funding from NIH grants DK099205, AA028550, DK101737, AA011999, DK120515, AA029019, DK091183; C.K.G received NIH grants DK091183 and HL147835. T.D.T. received support from NIH grants P30DK063491, T32DK007044, P30DK078392, the American Association for the Study of Liver Diseases (PNC23-216751), and the Center for Inflammation and Tolerance through the Cincinnati Children’s Research Foundation. R.L. had funding from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), the John C. Martin Foundation (RP124). J.M.O. got support from the Diabetes Research Center (P30DK063491) and the Horton JPI MRA: Obesity and its metabolic complications (20175015). A.E.F was funded by NIH grant R01DK113592. T.V.R received support from grants from the Swiss National Science Foundation (P2BSP3_200177) and the Larry L. Hillblom Foundation (2023-D-012-FEL).
