Itaconate derivative provides new approach to target JAK1 in potential asthma treatment

Itaconate and its derivative 4-octyl itaconate inhibit the Januse kinase 1 immune protein, which has implications for potential severe asthma treatment, according to a study published in Cell Metabolism.

“My lab is interested in the metabolite itaconate and derivatives based on it, which have a range of anti-inflammatory effects,” Luke A.J. O’Neill, PhD, chair of biochemistry at the Trinity College Dublin School of Biochemistry and Immunology, told Healio.

Luke A.J. O’Neill

“M2 macrophages, which are involved in asthma pathogenesis, can take up itaconate, and so we wondered what effect it might have on M2 macrophage function,” O’Neill said.

Cytokines IL-4 and IL-13, which O’Neill said are implicated in the pathogenesis of asthma, signal through the Janus kinase 1 (JAK1) immune protein and the signal transducer and activator of transcription 6 (STAT6) pathway.

IL-4 and IL-13 then activate M2 macrophages, which play a role in certain immunologic diseases. For example, the researchers said, lung pathologies such as asthma and allergy include type 2 inflammatory responses characteristic of M2 macrophages and T helper 2 (Th2) cells.

By inhibiting the JAK1/STAT6 pathway downstream of IL-4, the researchers said, itaconate and 4-octyl itaconate (OI), which are produced by the body, block M2 polarization and could be used to treat type-2 immune-mediated diseases including allergy and asthma.

First, the researchers investigated the effect of OI on M2 murine macrophages derived from bone marrow and activated by IL-4, where OI inhibited the M2 gene expression induced by IL-4, as well as JAK1/STAT6 signaling and metabolic reprogramming. The researchers said the inhibition likely was at the level of JAK1 phosphorylation.

Next, the researchers tested whether underivatized itaconic acid could recapitulate OI’s inhibitory effects in macrophage alternative activation and found that itaconic acid by itself inhibited the polarization of M2 macrophages similarly to OI.

Additional examination of JAK1 activation revealed that OI suppressed M2 macrophage effector genes and JAK1 phosphorylation both through IL-4 and IL-13 stimulation. OI also broadly inhibited JAK1 phosphorylation even outside of M2 polarization, providing further evidence for inhibition of JAK1 activation by OI upon cytokine signaling.

JAK1, then, may be a key cellular signaling component inhibited by OI, the researchers wrote. Based on the inhibition of JAK1 phosphorylation in IL-4, IL-13, interferon gamma-stimulated macrophages and Th2 cells by itaconate and OI, the researchers wrote, there may be a direct effect on JAK1.

Finally, the researchers explored whether OI had similar M2 inhibitory effects in mice injected with the itaconate derivative, where it inhibited the IL-4 signaling pathway, M2 polarization and JAK1 activation in two different in vivo models.

“We have found a new way to inhibit JAK1 via an endogenous module — itaconate, and also OI — which could lead to a new therapeutic approach for severe asthma,” said O’Neill. “We were somewhat surprised by how effective OI was in the in vivo model of asthma, which is steroid resistant. OI was very effective in the model.”

The researchers concluded that itaconate derivatives may be potent and safe pharmacological agents for treating asthma, allergy and other inflammatory diseases driven by alternative macrophage activation, although such treatment is still in the future.

“OI itself is not a therapeutic. It’s what’s called a tool compound,” O’Neill said. “However, molecules based on it are in development, and these could be useful as a treatment for severe steroid-resistant asthma.”

Next, O’Neill said, research will focus on analysis of compounds based on OI that could become therapeutics.

Reference:

• Trinity researchers discover new therapeutic target for severe asthma. https://www.tcd.ie/news_events/articles/trinity-researchers-discover-new-therapeutic-target-for-severe-asthma/. Published March 2, 2022. Accessed March 15, 2022.

For more information:

Luke A.J. O’Neill, PhD, can be reached at laoneill@tcd.ie.