Salt-inducible kinases (SIK) may be a novel therapeutic target for inflammation in autoimmune diseases such as Crohn’s disease, psoriasis, and arthritis, according to a report published in the Journal of Leukocyte Biology, titled “SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces anti-inflammatory phenotype.“
Macrophages are cells from the innate immune system that can perform multiple tasks, such as host defense, tissue repair, and resolve inflammation, depending on their activation state. Macrophages can be activated towards a pro-inflammatory or an anti-inflammatory state, and are usually known as M1 or M2 macrophages, respectively.
In many chronic diseases, the sustained inflammation is a result of an impaired resolution of inflammation, which usually requires the switch of macrophages from a pro-inflammatory to an anti-inflammatory state.
Researchers from Switzerland’s University of Geneva School of Medicine have showed that the inhibition of SIKs, by giving cells two structurally unrelated SIK inhibitors or by targeting SIKs through an RNAi genetic interference approach, were able to significantly reduce the amount of pro-inflammatory molecules (TNF-alpha, IL-6, IL-1beta, and IL-12) produced by macrophages, and increase the secretion of the anti-inflammatory IL-10 molecule.
The direct use of anti-inflammatory molecules such as IL-10 in rheumatoid arthritis or Crohn’s disease has either revealed limited efficacy, or led to the development of side effects following systemic administration, revealing the need for alternative strategies that safely and efficaciously increase the local levels of IL-10.
“Our laboratory studies further expand and validate the potential therapeutic implications of the use of salt-inducible kinase inhibitors for the treatment of immune-mediated inflammatory diseases,” said Maria Stella Lombardi, Ph.D., the study’s first author, in a press release. “The development of novel potent, selective, and drug-like inhibitors of the these pathways will allow us in the near future to test them in animal models of chronic inflammatory and autoimmune diseases.”
John Wherry, Ph.D., deputy editor of the Journal of Leukocyte Biology, wrote, “This work has the potential to add a new class of therapeutics for inflammatory disorders that could be used in combination with other distinct therapies in hard-to-treat autoimmunity inflammatory conditions.”