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Home»News»Immune cell inflammation may be responsible for some severe symptoms in lysosomal storage diseases
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Immune cell inflammation may be responsible for some severe symptoms in lysosomal storage diseases

healthtostBy healthtostJuly 12, 2024No Comments3 Mins Read
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Immune Cell Inflammation May Be Responsible For Some Severe Symptoms
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Researchers at The Hospital for Sick Children (SickKids) have discovered that inflammation in an immune cell may be partly responsible for some severe symptoms in a group of rare genetic conditions called lysosomal storage diseases (LSDs).

LSD affects approximately one in 7,700 live births worldwide. Children with the condition usually present at a young age with progressive neurodegeneration. Many children with LSD die prematurely, and current treatments focus on symptom management.

Until now, the role of macrophages in the immune system and LSDs was not well known, but new research published in Nature Cell Biology led by Dr. Spencer Freeman, scientist in the Cell Biology program, Ruiqi Cai, senior postdoctoral fellow and first author of the study, and Ori Scott, Transitional Clinical Scientist in the Cell Biology program and Staff Physician in the Department of Immunology and Allergy, found that inflammation of macrophages may contribute to LSD symptoms.

Macrophage cells take in and digest a large amount of nutrients to help the immune system function normally. To break down and recycle these nutrients, cells rely on tiny organelles called lysosomes. When functional, a lysosome can break down large sugars into small sugars, which are then used as a source of energy. In LSDs, these macrophage lysosomes swell and fill with waste.

In publishing these findings, Freeman, Cai and Scott share how LSDs affect the immune system and how reducing inflammation could potentially improve or prevent symptoms in children on LSD.

What is different about macrophages in LSD patients?

In LSD macrophages, the swollen lysosomes try to avoid opening 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 an “SOS” signal by releasing a substance called MCP-1 (monocyte chemoattractant protein 1) that tells other macrophages: “please come help”. 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 tissue damage.

How can your findings help LSD patients?

Our findings suggest that blocking sodium channel or MCP-1 receptor in macrophages could reduce inflammation and tissue damage in LSDs. There are already drugs that target these molecules, some of which are used for other inflammatory conditions such as rheumatoid arthritis. We plan to test these drugs in preclinical models and hope to translate the results into clinical trials for LSD patients.

By studying what causes severe symptoms in children with LSD, we can identify better treatments for patients affected by these devastating conditions.

What are the next steps for your research?

We continue to investigate 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 lysosomal dysfunction and inflammation we can identify new targets for drug development and improve the quality of life of patients with LSD and other related conditions such as Parkinson’s disease.

When we study people with rare pediatric conditions, the benefits go beyond those individuals and their families and extend to everyone, improving our knowledge of the complexity of human biology.

This research was funded by the Canadian Institutes of Health Research (CIHR), the German Research Foundation, Hightech Agenda Bavaria, the European Research Council and the Metropolitan University of Toronto.

Source:

The Hospital for Sick Children

Journal Reference:

Cai, R., et al. (2024). Lysosomal stress sensing allows control of TFEB responses in macrophages. Nature Cell Biology. doi.org/10.1038/s41556-024-01459-y.

cell diseases immune inflammation lysosomal responsible severe Storage Symptoms
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