CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Tomohiro Koga, Christian M. Hedrich, Masayuki Mizui, Nobuya Yoshida, Kotaro Otomo, Linda A. Lieberman, Thomas Rauen, José C. Crispín, George C. Tsokos

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Abstract

Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α(CREM- α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

Original languageEnglish
Pages (from-to)2234-2245
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number5
DOIs
Publication statusPublished - 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Koga, T., Hedrich, C. M., Mizui, M., Yoshida, N., Otomo, K., Lieberman, L. A., Rauen, T., Crispín, J. C., & Tsokos, G. C. (2014). CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. Journal of Clinical Investigation, 124(5), 2234-2245. https://doi.org/10.1172/JCI73411