Cells have an internal skeleton that maintains their structure and also drives their movement. Known as the cytoskeleton, this scaffold is composed of a network of dynamic filaments made of a protein called actin. 

Given how important these structures are, alterations in the proteins that work together to build and control the actin cytoskeleton are often lethal or cause severe effects. For example, children born with mutations in the ARPC5 protein, which is part of the Arp2/3 complex, experience immunodeficiency and a high risk of fatal sepsis in early life. 

“This is a rare and devastating condition, and until recently, it wasn’t clear how these mutations lead to such severe illness,” says Michael Way, who runs the Cellular Signalling and Cytoskeletal Function Laboratory at the Crick. “The only known effective treatment would involve early bone marrow transplantation to replace the faulty immune cells with ones which have a healthy actin cytoskeleton.”

Systemic inflammation and the role of the microbiome

To address this gap, Michael and his team set out to investigate how mutations in ARPC5 cause the immune system to malfunction.

Reported in a study in Science, Luiz Vasconcellos and Shaina Chor Mei Huang in the lab investigated immune system function in mice with and without ARPC5 mutations, observing a striking difference between healthy and ARPC5-deficient mice.  

“The inflammation in adult mice with ARPC5 deficiency in the immune system mirrored what we see in people with the same mutation,” describes Shaina. “At eight weeks after birth, mice were underweight with inflamed and damaged small intestines. They also had sepsis, resulting from bacterial infiltration from the gut that the immune system couldn’t control.”

In contrast to adult mice, at four weeks after birth, ARPC5-deficient mice were healthy. 

“This time point coincides with weaning, when mice stop getting immune protection by feeding from their mother,” says Luiz. “This also involves a big change in the bacterial composition in their gut, collectively known as the microbiome. We next looked at whether the interaction between the immune system and the microbiome leads to the intestinal inflammation.” 

The team analysed the composition of the microbiome before and after weaning in ARPC5-deficient mice, confirming that the types of bacteria changed at four weeks, another piece of evidence that the microbiome is the trigger for the intestinal inflammation. They then gave antibiotics to the ARPC5-deficient mice at this critical four-week time point, which fully prevented the disease from ever developing. 

Immune cell dysfunction

Understanding the complexities of microbiome control required the team to take a deep dive into the interactions between different types of immune cells. 

“When we looked further into the immune system of ARPC5-deficient mice, we saw that the crosstalk between macrophages and T regulatory cells had broken down, leading to the loss of the immune ‘status quo’,” Luiz explains. 

“We also saw that macrophages had lost their usual shape, becoming elongated, and could no longer eat or kill bacteria effectively,” Shaina adds.

Finally, the team showed that replacing these faulty immune cells in the mice via a bone marrow transplant reversed the inflammation, suggesting that people lacking ARPC5 would also likely benefit from the same treatment.

Outlook for patients

“We now know that immune cells with key structural deficiencies are unable to respond in the right way to gut microbes, and this leads to the problems seen in patients,” says Michael. “But structurally deficient macrophages are present in many other conditions, including inflammatory bowel disease. We’re also now looking at ARPC5-deficient macrophages in other parts of the body, like the lung.” He concludes, “I think we’re just scratching the surface of how important the cytoskeleton is for maintaining a functioning immune system.