A new connective tissue protein known to support the organ frame also boosts immune responses that fight bacterial infections, while restricting responses that can be deadly in the condition called sepsis, according to a new study.
Led by researchers at the NYU Grossman School of Medicine, the work revolves around the extracellular matrix (ECM) of connective tissues, once thought of as an inert framework that shapes body compartments, but increasingly recognized as a signaling partner with nearby cells in normal function, and contributes to the disease when the signals are twisted. Among the key players in ECM are fibroblasts, the cells which manufacture resistant structural matrix proteins such as collagen.
Published online June 28 at Proceedings of the National Academy of Sciences, the new analysis found that lumican, a protein-the combination of sugar (proteoglycan) secreted by fibroblasts and known to collaborate with collagen in connective tissues, also promotes immune system responses in immune cells called macrophages that fight bacterial infections. At the same time, the study found that luminescence protects tissues by restricting a different type of immune response which reacts to DNA, either from an invasive virus or from human cells they shed their DNA as they die (a sign that tissues are under stress).
These inflammatory responses represent a transition to healing, but they grow too much in sepsis, damaging the body’s own tissues to the point of organ failure. According to the authors, sepsis affects 48.9 million people worldwide, but the role of ECM in this disease is largely unknown.
“Lumican may play a dual protective role in ECM tissues, promoting defense against bacteria on the one hand and limiting excessive immune reactions in DNA that cause self-attacks or autoimmunity,” he says. the corresponding author of the study Shukti Chakravarti, Ph.D. D., professor in the departments of Ophthalmology and Pathology at NYU Langone Health.
The findings suggest that connective tissue, and extracellular matrix proteins, such as lumican, function outside of cells normally, but as disease or damage break down the ECM, they suck up and regulate immune cells that affect the damage.
Maintain balance
The study authors claim that Lumican interacts with two proteins on the surfaces of immune cells that control the activity of so-called toll-like receptors that recognize common structural patterns in molecules produced by microbial invasion. Because they are less specific than other parts of the immune system, toll-like receptors it can also cause immune cell attacks on the body’s own tissues if over-activated.
The authors of the current study found that lumican promotes the ability of the toll-like receptor (TLR) -4 on the surfaces of immune cells to recognize bacterial cell wall toxins called lipopolysaccharides (LPS). Specifically, the study found that lumican, by adhering to two proteins, CD14 and Caveolin1, which probably use regions normally covered in collagen, stabilizes its interactions with TLR4 to increase its ability to react to LPS. In turn, this leads to the production of TNF alpha, a signaling protein that amplifies immune responses.
Along with the description of the effect of lumicane on the surfaces of immune cells, the new study finds that lumicane is extracted from external cells in membrane-bound sacs called endosomes and extracted into the cells. cells. These compartments supply ingested bacteria to other endosomes that destroy them or increase inflammation or protective responses to interferon. Once stretched inward, the researchers found that lumican enhanced TLR4 activity by slowing its passage to lysosomes, bags where these proteins break down and recycle.
Although it stimulated TLR4 activity on cell surfaces, lumican, once inside immune cells, had the opposite effect on the toll-like receptor 9 (TLR9), which is known reacts to DNA instead of bacterial LPS. Experiments showed that lumican binding of DNA to endosomes keeps it away and prevents it from activating, TLR9.
The experiments confirmed that mice designed because they do not have the Lumican gene have problems both in fighting bacterial infections (less cytokine response, slower deployment, more weight loss) and in restricting the immune response to bacteria (sepsis). The study authors also found elevated levels of lumica in the blood plasma of patients with human sepsis and that human immune cells (blood monocytes) treated with lumica had high TLR4 activity, but suppressed TLR9 responses. .
“As an influencer of both processes, lumican-based peptides could be used as a lever to adjust inflammation related to TNF-alpha or endosomal interferon responses, to better resolve inflammation and infections,” he says. George Maiti, Ph.D., a postdoctoral fellow in Chakravarti’s laboratory. “Our results advocate a new role for ECM proteins in injury sites. Taken by entry immune cells it shapes immune responses beyond the cell surface by regulating movement and the interaction of endosomal receptors and signaling partners, ”he says.
George Maiti et al., “Immune cell endocyted lumican matrix controls receptor ligand trafficking to promote TLR4 and restrict TLR9 to sepsis.” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100999118
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Citation: Connective Tissue Protein Fights Bacterial Infections (2021, June 28) Retrieved June 28, 2021 at https://medicalxpress.com/news/2021-06-tissue-protein-bacterial-infection.html
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