title: CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance.
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.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Kotaro
authors.initials: K
authors.lastname: Otomo
authors.forename: Linda A
authors.initials: LA
authors.lastname: Lieberman
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: José C
authors.initials: JC
authors.lastname: Crispín
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C497410:CREM protein, human; C497411:Crem protein, mouse; C508717:IL17A protein, human; C440021:IL17F protein, human; C098680:Il17a protein, mouse; C515932:Il17f protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger; D051786:Cyclic AMP Response Element Modulator; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse