Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth

Abstract Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn,...

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Autores principales:	Yi-Jun Wang, Matthew A. Downey, Sungwoon Choi, Timothy M. Shoup, David R. Elmaleh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e2328ab4abee4ebfb166ab93580cbe93
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spelling	oai:doaj.org-article:e2328ab4abee4ebfb166ab93580cbe932021-11-14T12:19:34ZCromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth10.1038/s41598-021-00465-62045-2322https://doaj.org/article/e2328ab4abee4ebfb166ab93580cbe932021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00465-6https://doaj.org/toc/2045-2322Abstract Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Furthermore, cromolyn and F-cromolyn augment neurite outgrowth in PC12 neuronal cells in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.Yi-Jun WangMatthew A. DowneySungwoon ChoiTimothy M. ShoupDavid R. ElmalehNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yi-Jun Wang Matthew A. Downey Sungwoon Choi Timothy M. Shoup David R. Elmaleh Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
description	Abstract Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Furthermore, cromolyn and F-cromolyn augment neurite outgrowth in PC12 neuronal cells in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.
format	article
author	Yi-Jun Wang Matthew A. Downey Sungwoon Choi Timothy M. Shoup David R. Elmaleh
author_facet	Yi-Jun Wang Matthew A. Downey Sungwoon Choi Timothy M. Shoup David R. Elmaleh
author_sort	Yi-Jun Wang
title	Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
title_short	Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
title_full	Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
title_fullStr	Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
title_full_unstemmed	Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
title_sort	cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e2328ab4abee4ebfb166ab93580cbe93
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Cromolyn platform suppresses fibrosis and inflammation, promotes microglial phagocytosis and neurite outgrowth

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