A team of Northwestern Medicine scientists have discovered that a specific type of immune cell called tissue-resident macrophage is necessary for the suppression of chronic inflammation, revealing a potential therapeutic target for rheumatoid arthritis, according to findings published in Science Advances.
“This study shows tissue-resident macrophages being the guardian of preventing inflammation and provides a novel way of thinking about treating patients with targeted therapy,” said Richard Pope, MD, the Solovy/Arthritis Research Society Professor, professor of Medicine in the Division of Rheumatology and co-senior author of the study.
Rheumatoid arthritis is an autoimmune disease in which the body’s immune system attacks its own tissue including the joints, causing chronic inflammation and painful swelling. The body’s inflammatory response is generated by monocytes — white blood cells produced in bone marrow — that move out of the body’s circulatory system and differentiate into macrophages, white blood cells found in all tissues that rid of pathogens and can perform either pro- or anti-inflammatory functions.
There are various types of macrophages; tissue-resident macrophages in the body’s synovial tissue specifically are responsible for ensuring proper joint health. In contrast, macrophages derived from peripheral blood monocytes initiate and perpetuate inflammation, but the exact molecular mechanisms involved have remained poorly understood.
Previous work from Pope’s laboratory found that a specialized protein called FLIP (FLICE-like inhibitory protein) protects macrophages from apoptosis, or cell death, and have been found to be highly expressed in macrophages of patients with rheumatoid arthritis.
Using this knowledge to inspire the current study, the investigators deleted FLIP from tissue-resident macrophages in mouse models of rheumatoid arthritis with the aim of ameliorating the disease. However, in this case, the investigators found that deleting FLIP actually promoted chronic inflammation in the mice by preventing monocytes from differentiating into tissue-resident macrophages.
“A big part of this transition from monocytes to tissue-resident macrophages has to do with how genes are regulated, and one of our goals is to identify which proteins, known as transcription factors, regulate these sets of genes,” Winter said.
To cement their findings, the investigators linked the circulatory systems of two populations of mice — one with rheumatoid arthritis and one without. Using flow cytometry and functional studies, they found that healthy monocytes from the mice without rheumatoid arthritis were able to successfully enter into the joints of the mice with the disease, become tissue-resident macrophages and suppress inflammation.
“These results confirmed that it was the inability of macrophages in the mice with arthritis to undergo this transition that led to disease,” Winter said.
According to the authors, the results are consistent with previous work showing that monocytes in patients with rheumatoid arthritis have an epigenetic modification that prevent them from differentiating into tissue-resident macrophages and ameliorating chronic inflammation in the joints. The findings also align with previous work showing that as humans age, tissue-resident macrophages decrease and the risk of inflammation increases.
Additionally, the study debunks the long-standing idea that all macrophages are “bad” and only promote inflammation, according to Winter.
“If we want to treat people or prevent disease, we can’t just get rid of all macrophages,” Winter said. “We want to promote macrophages that are good for the joints and possibly reprogram the ones that aren’t good.”
Pope also added that the team hopes to determine if non-classical monocytes — critical for patrolling and protecting blood vessels — are in fact entering the joints and causing disease rather than classical monocytes, which have been previously thought to have pro-inflammatory properties but when targeted and neutralized provided no clinical benefit.
Qi-Quan Huang, MD, research professor of Medicine in the Division of Rheumatology, was first author of the study. Co-authors include Alexander Misharin, MD, PhD, assistant professor of Medicine in the Division of Pulmonary and Critical Care, and Qinwen Mao, MD, PhD, associate professor of Pathology in the Division of Neuropathology. Misharin and Mao are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was supported by National Institutes of Health grants R01AR070025, AR048269, HL135124, AG049665 and AI135964, the Solovy/Arthritis Research Society Endowment, the Arthritis National Research Foundation, the American Lung Association grant 514724, the Scleroderma Foundation, the American Federation for Aging, American Heart Association grant 18CDA34110224, and an ATS Foundation/Mallinckrodt Pharmaceuticals Research Fellowship and Department of Defense grant PR141319.