Restoration of Macrophage Function as a Strategy to Prevent/Treat Lupus
Abstract
Lupus is a highly complex disease, and very difficult to prevent or treat effectively and safely. Women are much more likely to develop lupus than men, but the reasons for this difference are still not completely understood. Hormones clearly play a role; however, more recently accumulating evidence suggests that the gut microbiota (the beneficial bacteria that live in the gut) may have a significant effect on development and progression of lupus. In our preliminary studies, we have found that fecal transplants (i.e., feeding gut microbiota/bacteria) from male (lupus-resistant) mice to female (lupus-susceptible) mice suppress disease (lupus nephritis) and increase survival in the recipients. We would like to understand how this male microbiota protects female mice from disease, and we have identified a molecule ( a metabolite) that the male gut bacteria produce that may be involved in the protection. Patients with lupus have problems with many different types of white blood cells. One of type of white blood cells that may not only help cause the disease, but may also help make it worse, is a cell called the macrophage. Macrophages are scavenger (trash-collecting) cells whose job is to remove dead cells in healthy people. However, these cells do not work very well in lupus patients. The result is the accumulation of dead cells that then activate other white blood cells resulting in the production of anti-nuclear antibodies (ANA) and other types of antibodies. ANAs and the other antibodies can get stuck in important organs such as the kidneys and cause dangerous inflammation and damage. Our female mice have a very similar problem with their macrophage function that also results in production of ANAs and ultimately, in fatal lupus nephritis. The male microbiota-associated metabolite that we have identified is able to significantly improve macrophage function in female mice so that they are capable of removing dead cells (trash collecting) very effectively. We believe that improving macrophage function could prevent the development of disease in at-risk individuals and/or control progression of disease in patients with established disease. In this proposal, we plan to study how our metabolite improves macrophage function in our mouse model of lupus, and very importantly, determine whether it has similar effects on white blood cells from patients with active lupus nephritis. We will test these effects with white blood cells from both mice and lupus patients in culture and also directly in the mice themselves, using state-of-the-art technology. This metabolite has low toxicity and is a natural constituent of red meat, dairy products, and some fish. We believe that this metabolite either alone, or possibly in combination with other therapies, has great potential to be developed into a therapy for the prevention and/or treatment of active lupus.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310377
Entities
People
- Michele Kosiewicz
Organizations
- United States Army
- University of Louisville