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Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity
Author(s) -
Basler Michael,
Lindstrom Michelle M,
LaStant Jacob J,
Bradshaw J Michael,
Owens Timothy D,
Schmidt Christian,
Maurits Elmer,
Tsu Christopher,
Overkleeft Herman S,
Kirk Christopher J,
Langrish Claire L,
Groettrup Marcus
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201846512
Subject(s) - experimental autoimmune encephalomyelitis , autoimmunity , proteasome , immunology , secretion , major histocompatibility complex , autoimmune disease , colitis , biology , chemistry , microbiology and biotechnology , antigen , inflammation , immune system , antibody , biochemistry
Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine‐inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL‐1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre‐clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7‐specific inhibitor, has limited effects on IL‐6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co‐inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU‐001i or ML604440 impairs MHC class I cell surface expression, IL‐6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co‐inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.