TY - JOUR
T1 - Small heat shock proteins, amyloid fibrils, and nicotine stimulate a common immune suppressive pathway with implications for future therapies
AU - Rothbard, Jonathan B.
AU - Kurnellas, Michael P.
AU - Ousman, Shalina S.
AU - Brownell, Sara
AU - Rothbard, Jesse J.
AU - Steinman, Lawrence
N1 - Funding Information:
Lieb (mass spectrometry), Bianca Gomez (flow cytometry), and Kitty Lee (confocal microscopy) without whom this story could not have been written. This work was supported in part by grants from the National Multiple Sclerosis Society.
Publisher Copyright:
© 2019 Cold Spring Harbor Laboratory Press.
PY - 2019/7
Y1 - 2019/7
N2 - The α7 nicotinic acetylcholine receptor (α7nAChR) is central to the anti-inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological role of αB-crystallin (HspB5), the most abundant gene transcript present in active multiple sclerosis lesions in human brains, also led to α7nAChR. Induction of experimental autoimmune encephalomyelitis (EAE) in HspB5-/- mice results in greater paralytic signs, increased levels of proinflammatory cytokines, and T-lymphocyte activation relative to wild-type animals. Administration of HspB5 was therapeutic in animal models of multiple sclerosis, retinal and cardiac ischemia, and stroke. Structure-activity studies established that residues 73-92 were as potent as the parent protein, but only when it formed amyloid fibrils. Amyloid fibrils and small heat shock proteins (sHsps) selectively bound α7nAChR on peritoneal macrophages (Mφs) and B lymphocytes, converting the Mφs to an immune suppressive phenotype and mobilizing the migration of both cell types fromthe peritoneum to secondary lymph organs. Here,we review multiple aspects of this work, which may be of interest for developing future therapeutic approaches for multiple sclerosis and other disorders.
AB - The α7 nicotinic acetylcholine receptor (α7nAChR) is central to the anti-inflammatory function of the vagus nerve in a physiological mechanism termed the inflammatory reflex. Studies on the inflammatory reflex have been instrumental for the current development of the field of bioelectronic medicine. An independent investigation of the biological role of αB-crystallin (HspB5), the most abundant gene transcript present in active multiple sclerosis lesions in human brains, also led to α7nAChR. Induction of experimental autoimmune encephalomyelitis (EAE) in HspB5-/- mice results in greater paralytic signs, increased levels of proinflammatory cytokines, and T-lymphocyte activation relative to wild-type animals. Administration of HspB5 was therapeutic in animal models of multiple sclerosis, retinal and cardiac ischemia, and stroke. Structure-activity studies established that residues 73-92 were as potent as the parent protein, but only when it formed amyloid fibrils. Amyloid fibrils and small heat shock proteins (sHsps) selectively bound α7nAChR on peritoneal macrophages (Mφs) and B lymphocytes, converting the Mφs to an immune suppressive phenotype and mobilizing the migration of both cell types fromthe peritoneum to secondary lymph organs. Here,we review multiple aspects of this work, which may be of interest for developing future therapeutic approaches for multiple sclerosis and other disorders.
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U2 - 10.1101/cshperspect.a034223
DO - 10.1101/cshperspect.a034223
M3 - Article
C2 - 30249602
AN - SCOPUS:85069261478
SN - 2157-1422
VL - 9
JO - Cold Spring Harbor Perspectives in Medicine
JF - Cold Spring Harbor Perspectives in Medicine
IS - 7
M1 - a034223
ER -