Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice.
Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.
Biswas
Partha S
PS
Department of Medicine, Columbia University, New York, New York, USA.
Gupta
Sanjay
S
Chang
Emily
E
Song
Li
L
Stirzaker
Roslynn A
RA
Liao
James K
JK
Bhagat
Govind
G
Pernis
Alessandra B
AB
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000276:immunology* / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D020381:Interleukin-17; D007378:Interleukins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000098546:Interleukin-21; D000099218:Interferon Regulatory Factor-4; C515855:Rock2 protein, mouse