Researchers at the Hospital for Sick Children (SickKids) have uncovered that inflammation in macrophages may be responsible in part for some severe symptoms in a group of rare genetic conditions called lysosomal storage diseases (LSDs).
LSDs affect about one in 7,700 live births worldwide. Children with the condition typically present at a young age with progressive neurodegeneration. Many children with LSDs die prematurely, and current treatments focus on symptom management.
The role of macrophages in the immune system and LSDs was not well known, but the new research published in Nature Cell Biology in an article titled, “Pressure sensing of lysosomes enables control of TFEB responses in macrophages.”
“Polymers are endocytosed and hydrolyzed by lysosomal enzymes to generate transportable solutes,” the researchers wrote. “While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tabulation, and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol.”
The study, led by Spencer Freeman, PhD, a scientist in the cell biology program, Ruiqi Cai, PhD, a senior postdoctoral fellow and the first author of the study, and Ori Scott, MD, PhD, a transition clinician scientist in the cell biology program and a staff physician in the division of immunology and allergy, identified that macrophage inflammation may contribute to LSD symptoms.
The researchers uncovered how LSDs affect the immune system and how reducing inflammation could potentially improve or prevent symptoms in children with LSDs.
In LSD macrophages, swollen lysosomes try to avoid bursting open and spilling their contents, which would cause the cell to die. To do this, lysosomes open a channel that moves sodium out of the lysosomes, followed by water, to keep them smaller. This creates a message: the lysosome and the cell are stressed.
The stressed macrophages then send out an “SOS” signal by releasing a substance called MCP-1 (monocyte chemoattractant protein 1) that calls other macrophages to their aid. As a result, many more macrophages move into the tissue. When there are too many macrophages in a tissue, and they all secrete MCP-1, this can cause inflammation and damage to the tissue.
Their findings suggest that blocking the sodium channel or the MCP-1 receptor in macrophages could reduce the inflammation and tissue damage in LSDs. There are already drugs that target these molecules. The researchers are planning to test these drugs in preclinical models, and hope to translate the results to clinical trials for patients with LSDs.
They are continuing to explore how the lysosome regulates macrophage function and inflammation in LSDs and other conditions including neurodegenerative diseases. “We hope that by understanding the molecular mechanisms of lysosome dysfunction and inflammation we can identify novel targets for drug development and improve the quality of life of patients with LSDs and other related conditions, like Parkinson’s disease,” concluded the researchers.
