Scientists working in the School of Biochemistry and Immunology at the Trinity Biomedical Sciences Institute (TBSI) report they have uncovered a new strategy in mice for treating severe asthma. The researchers hope these new findings have the potential to be a new therapeutic approach as there is an urgent need for new treatments.
Their findings are published in the journal, Cell Metabolism, in a paper titled, “Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.”
“The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory ‘M1’ macrophages,” the researchers wrote. “However, alternatively activated ‘M2’ macrophages can take up itaconate. We, therefore, examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling.”
“We have found that a molecule made by our own bodies, called itaconate, can suppress key events that promote asthma by targeting an important immune protein called JAK1,” explained Luke O’Neill, lead investigator and professor of biochemistry at Trinity. “By shutting off JAK1 we have shown remarkable efficacy in lab-based models of asthma.”
The protein JAK1 is important in driving the immune response. However, excessive stimulation causes inflammation and is problematic in conditions such as asthma.
“Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI,” noted the researchers. “JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells.”
“We tested a molecule called 4-OI, which is based on itaconate, and it was able to suppress severe asthma in a model of the disease which doesn’t respond to anti-inflammatory steroids. We, therefore, hope our findings might pave the way for new treatments, especially in children.”
The researchers hope that these new findings can have the potential to be a new therapeutic approach for treating severe asthma, where there is an urgent need for new treatments.