NFAT control of innate immunity by Jan Fric, Teresa Zelante, Alicia Y. W. Wong, Alexandra Mertes, Hong-Bing Yu, and Paola Ricciardi-Castagnoli Blood Volume 120(7):1380-1389 August 16, 2012 ©2012 by American Society of Hematology

Calcineurin/NFAT-dependent IL-2 release in DCs Calcineurin/NFAT-dependent IL-2 release in DCs. DCs produce IL-2 early after encountering bacterial or fungal cell wall components. Calcineurin/NFAT-dependent IL-2 release in DCs. DCs produce IL-2 early after encountering bacterial or fungal cell wall components. Ligand binding to dectin 1 signals through ITAM-like motifs, leading to the recruitment of Syk family kinases and Ca2+ influx, which culminates in NFAT translocation to the nucleus, gene transcription, and extracellular release of IL-2 cytokine. Alternatively, ligand binding to CD14 requires collaboration of MD2 and Src-family kinases (SFKs) with TLR4 molecule to initiate this pathway. Jan Fric et al. Blood 2012;120:1380-1389 ©2012 by American Society of Hematology

NFAT signaling in DCs in response to microbes, TLR ligands, and particulates. NFAT signaling in DCs in response to microbes, TLR ligands, and particulates. Schematic representation of a DC activated by different stimuli. Microbial stimuli, both bacterial and fungal, activate Ca2+ flux, which promotes NFAT dephosphorylation through close collaboration with TLR signaling. Stimulation also occurs in response to particulate β-glucan, being recognized by the dectin 1 clusters that are required for Syk pathway activation and NFAT nuclear translocation. Jan Fric et al. Blood 2012;120:1380-1389 ©2012 by American Society of Hematology

Effects of calcineurin/NFAT inhibitors on myeloid innate immune cells. Effects of calcineurin/NFAT inhibitors on myeloid innate immune cells. Treatment with CsA, tacrolimus, or VIVIT affects the myeloid cells at different levels. Inhibition of NFAT enhances the development of myeloid cells from hematopoietic precursors as well as several immune functions in differentiated cell types. After exposure to different PAMPs, innate myeloid cells respond by activating NFAT and transcribing downstream genes, resulting in modulation of proinflammatory and prosurvival gene programs. Treatment with CsA or tacrolimus during the response to microbial stimuli decreases NFAT nuclear translocation, leading to changes in inflammatory status of different types of myeloid cells, eventually exacerbating or protecting from infections or inflammatory syndromes. Jan Fric et al. Blood 2012;120:1380-1389 ©2012 by American Society of Hematology