TY - JOUR
T1 - Fyn kinase mediates pro-inflammatory response in a mouse model of endotoxemia
T2 - Relevance to translational research
AU - Saminathan, Hariharan
AU - Charli, Adhithiya
AU - Luo, Jie
AU - Panicker, Nikhil
AU - Gordon, Richard
AU - Hostetter, Jesse M.
AU - Jin, Huajun
AU - Anantharam, Vellareddy
AU - Kanthasamy, Anumantha G.
AU - Kanthasamy, Arthi
N1 - Funding Information:
This work was funded by the National Institutes of Health ( NIH ) grants NS088206 , ES026892 and NS100090 . Other sources include Lloyd endowed chair and Eminent Scholar and Armbrust Endowment to AGK and Salsbury endowed chair to AK.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/8/15
Y1 - 2020/8/15
N2 - Systemic inflammation resulting from the release of pro-inflammatory cytokines and the chronic activation of the innate immune system remains a major cause of morbidity and mortality in the United States. After having demonstrated that Fyn, a Src family kinase, regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson's disease, we investigate here its role in modulating systemic inflammation using an endotoxic mouse model. Fyn knockout (KO) and their wild-type (WT) littermate mice were injected once intraperitoneally with either saline or 5 mg/kg lipopolysaccharide (LPS) and were killed 48 h later. LPS-induced mortality, endotoxic symptoms and hypothermia were significantly attenuated in Fyn KO, but not WT, mice. LPS reduced survival in Fyn WT mice to 49% compared to 84% in Fyn KO mice. Fyn KO mice were also protected from LPS-induced deficits in horizontal and vertical locomotor activities, total distance traveled and stereotypic movements. Surface body temperatures recorded at 24 h and 48 h post-LPS dropped significantly in Fyn WT, but not in KO, mice. Importantly, endotoxemia-associated changes to levels of the serum pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), splenocyte apoptosis and inducible nitric oxide synthase (iNOS) production in hepatocytes were also significantly attenuated in Fyn KO mice. Likewise, pharmacologically inhibiting Fyn with 10 mg/kg dasatinib (oral) significantly attenuated LPS-induced increases in plasma TNF-α and IL-6 protein levels and hepatic pro-IL-1β messenger ribonucleic acids (mRNAs). Collectively, these results indicate that genetic knockdown or pharmacological inhibition of Fyn dampens systemic inflammation, demonstrating for the first time that Fyn kinase plays a critical role in mediating the endotoxic inflammatory response.
AB - Systemic inflammation resulting from the release of pro-inflammatory cytokines and the chronic activation of the innate immune system remains a major cause of morbidity and mortality in the United States. After having demonstrated that Fyn, a Src family kinase, regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson's disease, we investigate here its role in modulating systemic inflammation using an endotoxic mouse model. Fyn knockout (KO) and their wild-type (WT) littermate mice were injected once intraperitoneally with either saline or 5 mg/kg lipopolysaccharide (LPS) and were killed 48 h later. LPS-induced mortality, endotoxic symptoms and hypothermia were significantly attenuated in Fyn KO, but not WT, mice. LPS reduced survival in Fyn WT mice to 49% compared to 84% in Fyn KO mice. Fyn KO mice were also protected from LPS-induced deficits in horizontal and vertical locomotor activities, total distance traveled and stereotypic movements. Surface body temperatures recorded at 24 h and 48 h post-LPS dropped significantly in Fyn WT, but not in KO, mice. Importantly, endotoxemia-associated changes to levels of the serum pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), splenocyte apoptosis and inducible nitric oxide synthase (iNOS) production in hepatocytes were also significantly attenuated in Fyn KO mice. Likewise, pharmacologically inhibiting Fyn with 10 mg/kg dasatinib (oral) significantly attenuated LPS-induced increases in plasma TNF-α and IL-6 protein levels and hepatic pro-IL-1β messenger ribonucleic acids (mRNAs). Collectively, these results indicate that genetic knockdown or pharmacological inhibition of Fyn dampens systemic inflammation, demonstrating for the first time that Fyn kinase plays a critical role in mediating the endotoxic inflammatory response.
KW - Apoptosis
KW - Cytokines
KW - Endotoxemia
KW - LPS
KW - Locomotor deficits
KW - Parkinson's disease
KW - Sepsis
KW - Systemic inflammation
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UR - http://www.scopus.com/inward/citedby.url?scp=85086792086&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2020.173259
DO - 10.1016/j.ejphar.2020.173259
M3 - Article
C2 - 32565338
AN - SCOPUS:85086792086
SN - 0014-2999
VL - 881
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
M1 - 173259
ER -