Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.
Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17-producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity.
Tran
Elise H
EH
Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Azuma
Yasu-Taka
YT
Chen
Manchuan
M
Weston
Claire
C
Davis
Roger J
RJ
Flavell
Richard A
RA
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D001921:Brain / Q000276:immunology* / Q000473:pathology; D003433:Crosses, Genetic; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics* / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D016753:Interleukin-10; D005620:Freund's Adjuvant; D048055:Mitogen-Activated Protein Kinase 8