Abstract
The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.
Highlights
Macrophages play diverse roles in the immune response due to their innate ability to adapt their physiology to the changing needs of the host [1,2,3]
The brain is unique among the tissues tested because SIK3 was the most abundant isoform while, in adipose tissue, kidney and macrophages, SIK2 made the greatest contribution to total salt-inducible kinase (SIK) kinase activity (Figure 1C)
Mutation of one isoform of the SIKs did not affect the overall expression or activity of the other two isoforms. These results indicate that the antibodies selectively immunoprecipitate the relevant isoform of the SIK against which it was raised and that endogenous SIK1, SIK2 and SIK3 do not hetero-oligomerize in mammalian cells
Summary
Macrophages play diverse roles in the immune response due to their innate ability to adapt their physiology to the changing needs of the host [1,2,3]. In response to infection or tissue damage, macrophages acquire an inflammatory phenotype characterized by the production of high levels of pro-inflammatory cytokines, such as tumour necrosis factor α (TNF-α), interleukin (IL)-12 and IL-1, a state often referred to as ‘classically activated’ or M1 macrophages. Various factors, including apoptotic neutrophils, immune complexes, IL-10 and prostaglandin E2 (PGE2), have been shown to promote diverse but related anti-inflammatory, pro-resolution phenotypes in macrophages, which have previously been grouped into M2 subsets [1,5]. The capacity of these subsets to modulate the immune response in vivo was demonstrated by showing that injection of these macrophage populations could protect mice from endotoxic shock [6]. Since the persistent presence of inflammatory macrophages is a feature of several human diseases, including rheumatoid arthritis and atherosclerosis [7–9], understanding the signalling pathways controlling the switch from inflammatory M1 to pro-resolution M2-like macrophages may identify new therapeutic strategies for the treatment of these diseases
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