Connective Tissue Protein Has Immune Role
A new study finds that a connective tissue protein also encourages immune responses that fight bacterial infections, while restraining responses that can be deadly in sepsis.
The study focuses on the extracellular matrix (ECM) of connective tissues, once viewed merely as structural material. It is now increasingly recognised as a signaling partner with nearby cells in normal function, as well as being involved in disease. Fibroblasts are important players in the ECM; these cells make tough structural matrix proteins like collagen. The study was published online June 28 in the Proceedings of the National Academy of Sciences.
The new analysis found that lumican, a protein-sugar combination (proteoglycan) secreted by fibroblasts, and known to partner with collagen in connective tissues, also promotes immune system responses in immune cells called macrophages that fight bacterial infections. The study also found that lumican protects tissues by holding back a different type of immune response that reacts to DNA, whether from an invading virus, or released from cell death.
Such inflammatory responses are a transition into healing, but in sepsis they grow out of control, causing damage to the body’s own tissues. Sepsis affects 48.9 million people worldwide, the authors said, but the ECM’s role the condition is largely unknown.
“Lumican may have a dual protective role in ECM tissues, promoting defense against bacteria on the one hand, and on the other, limiting immune overreactions to DNA that cause self-attack, or autoimmunity,” said corresponding study author Shukti Chakravarti, PhD, professor in the Department of Ophthalmology and the Department of Pathology at NYU Langone Health.
The findings suggest that connective tissue, and extracellular matrix proteins like lumican, usually operate outside of cells, but as disease or damage break down ECM, get sucked into and regulate immune cells homing in on the damage.
Lumican interacts with two proteins on surfaces of immune cells that control the activity of toll-like receptors, which recognise structural patterns common to molecules made by invading microbes, said the researchers. As they are less specific than other parts of the immune system, toll-like receptors can also cause attacks by immune cells on the body’s own tissues if over-activated.
In this study, the researchers found that lumican promotes the ability of toll-like receptor (TLR)-4 on the surfaces of immune cells to recognise bacterial cell-wall toxins called lipopolysaccharides (LPS). Lumican, by attaching to two proteins, CD14 and Caveolin1, probably using collagen-covered regions, stabilises their interactions with TLR4 to increase its ability to react to LPS. This results in production of the signalling protein TNF alpha, which amplifies immune responses.
Along with describing the effect of lumican on the surfaces of immune cells, the new study finds that lumican is taken up from outside cells into membrane-bound pouches, called endosomes, and pulled into cells. Such compartments deliver ingested bacteria to other endosomes that destroy them, heighten inflammation, or produce protective interferon responses. Once pulled inside, the researchers found, lumican bolstered TLR4 activity by slowing down its passage into lysosomes, pockets where such proteins are broken down and recycled.
However, while it encouraged TLR4 activity on cell surfaces, lumican, once inside immune cells, had the opposite effect on toll-like receptor 9 (TLR9), which reacts to DNA instead of bacterial LPS.
Mice with the lumican gene deleted had trouble both fighting off bacterial infections (less cytokine response, slower clearance, greater weight loss), and trouble restraining the immune overreaction to bacteria (sepsis). Elevated lumican levels were also found in human sepsis patients’ blood plasma, and that human immune cells (blood monocytes) treated with lumican had elevated TLR4 activity but suppressed TLR9 responses.
“As an influencer of both processes, lumican-based peptides could be used as a lever, to tweak inflammation related to TNF-alpha, or endosomal interferon responses, to better resolve inflammation and infections,” suggested George Maiti, PhD, a postdoctoral fellow in Dr Chakravarti’s lab.
“Our results argue for a new role for ECM proteins at sites of injury. Taken up by incoming immune cells it shapes immune responses beyond the cell surface by regulating the movement and interaction of endosomal receptors and signaling partners,” said Dr Chakravarti.
Source: NYU Langone Health
Journal information: George Maiti et al., “Matrix lumican endocytosed by immune cells controls receptor ligand trafficking to promote TLR4 and restrict TLR9 in sepsis,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100999118
