Mapping the biological machinery of the inflammatory skin disease neutrophilic dermatosis offers multiple targets for treating inflammatory disorders.
A research team led by St. Jude Children’s Research Hospital immunologists has revealed a previously unknown immune machinery that goes awry to trigger the inflammatory disease neutrophilic dermatosis. Neutrophilic dermatoses are a heterogeneous group of autoinflammatory skin disorders that include Sweet’s syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis and may occur with cancers such as leukemia as well as infections or inflammatory bowel disease.

Currently, the only treatments for such disorders are strong immunosuppressive drugs that also render patients susceptible to infection.

The study was led by Thirumala–Devi Kanneganti, PhD, a member of the St. Jude Department of Immunology.

The findings appeared in the journal Immunity.

First authors were Prajwal Gurung, PhD, a postdoctoral fellow in the Kanneganti laboratory, and Gaofeng Fan, PhD, of Cold Spring Harbor Laboratory.

Abnormalities in the PTPN6 gene have been implicated in human diseases such as pyoderma gangrenosum, multiple sclerosis, leukemia and psoriatic arthritis.

The researchers used a strain of gene–altered mouse in which the activity of a protein encoded by the Ptpn6 gene was “dialed down.” The mice developed inflammatory skin disease similar to neutrophilic dermatosis in humans. Like humans with the disorder, the mice appear normal when first born, but as they age, they developed the inflammatory disease.

How does disease ensue in the Ptpn6 mutant mice? What are the key pathways that are regulated by the Ptpn6 gene? Kanneganti and her colleagues previously discovered in a seminal study published in the journal Nature that IL–1 alpha is the key master regulator that provokes uncontrolled immune response in the Ptpn6 mutant mice. But the machinery linking Ptpn6 and IL–1 alpha was a “black box,” Kanneganti said.

To map the machinery, the researchers took a genetic approach and painstakingly produced mice defective in Ptpn6 that additionally lacked candidate genes in the pathway. Here, the researchers knew that if the Ptpn6 mutant mice crossed with the mouse deficient in a candidate gene do not develop disease, they would be able to identify the gene that triggers aberrant inflammation and disease. After creating some 50 different combinations with different candidate genes, the researchers pieced together the puzzle of the immune machinery underlying the inflammation.

The picture they revealed further confirmed that IL–1 alpha is a master immune switch that activates the machinery. In addition, they also identified several key molecules including RIPK1, TNF, TAK1 and SYK that drive inflammation and tissue damage.

“This is quite an important finding,” Kanneganti said. “IL–1 alpha was discovered more than 45 years ago, but we have not known how it is regulated and how it functions. And our lab is one of the very few in the country studying IL–1 alpha.”

Another important finding is how different “cellular compartments” interact to trigger autoinflammatory disease. While the abnormal Ptpn6 gene functions in the bone marrow – a major source of disease instigating innate immune cells – the IL–1 alpha master switch functions in the skin.

Finally, the study unraveled how the Ptpn6 gene regulates IL–1 alpha mediated aberrant inflammation and disease. The researchers identified that Ptpn6 inhibited activation of a critical tyrosine kinase called SYK to modulate activation of a central adaptor protein MyD88, a previously unknown signaling node.