Anakinra Promotes M2 Microglia Activation during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

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Abstract

Astrocytes and microglia and their polarization are thought to contribute to the progression of epilepsy. One of the processes affecting polarization is neuroinflammation, which plays an important role in epileptogenesis. However, the specific mechanisms of its involvement in shifting the pro- and anti-inflammatory reactivation of astro- and microglia have not been clarified. In this study, we examined the effect of 7-day interleukin-1 receptor antagonist (anakinra) administration on glial cell polarization during the latent phase of the lithium-pilocarpine model in 7-week-old male Wistar rats. In temporal cortex, dorsal and ventral hippocampus the mRNA expression levels of the following genes were analyzed: (i) markers of astroglia (S100b) and microglia (Aif1) activation, (ii) astrocytic proteins involved in glutamate transport and metabolism (Slc1a3, Glul, Gja1), (iii) pro-inflammatory pathway interleukin-1β (Nlrp3, Il1b, Il1rn) and transforming growth factor β1 (Tgfb1), (iv) markers of astroglia polarization (Lcn2, S100a10, Gbp2, Ptx3), and (v) microglia polarization (Nos2 and Arg1). The mRNA expression levels of S100b and Aif1 were significantly increased, and anakinra administration did not reduce their overexpression. This indicates reactivation of astroglia and microglia regardless of the anakinra administered. The expression of Slc1a3, Glul, and Gja1 genes increased in the hippocampus; anakinra administration did not affect their hyperexpression, but promoted increased expression of Gja1 in the temporal cortex. The mRNA production of Lcn2, S100a10, Gbp2, Ptx3, Nlrp3, Il1b, Il1rn and Tgfb1 increased in all structures. Administration of anakinra reduced the gene expression of Il1b. Among the markers of microglia polarization, downregulation of Arg1 expression in the dorsal hippocampus and Nos2 expression in the temporal cortex was detected. Anakinra administration enhanced the decrease in Nos2 expression and restored the level of Arg1 expression to control values. Thus, anakinra administration did not affect the intensity of glial cell reactivation, but improved M2 reactivation of microglia.

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About the authors

M. V. Zakharova

Sechenov Institute of Evolutionary Physiology and Biochemistry

Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

A. V. Dyomina

Sechenov Institute of Evolutionary Physiology and Biochemistry

Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

A. A. Kovalenko

Sechenov Institute of Evolutionary Physiology and Biochemistry

Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

O. E. Zubareva

Sechenov Institute of Evolutionary Physiology and Biochemistry

Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

A. M. Ischenko

Saint-Petersburg Pasteur Institute

Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

A. V. Zaitsev

Sechenov Institute of Evolutionary Physiology and Biochemistry

Author for correspondence.
Email: aleksey_zaitsev@mail.ru
Russian Federation, St. Petersburg

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2. Fig. 1. Relative expression of astrocyte activation marker genes (S100b) and microglial cells (Aif1) in the temporal cortex (TC), dorsal (DH) and ventral (VH) hippocampus of rats 7 days after epileptic status. * p < 0.05, ** p < 0.01, *** p < 0.001 in ANOVA with the a posteriori Tukey criterion or ANOVA with the Welch correction and the a posteriori Games–Howell criterion. S100b: TC: F(2, 27) = 12.5, p = 0.002; DH: F(2, 23) = 18.9, p < 0.001; VH: F(2, 25) = 60.3, p < 0.001; Aif1: TC: F(2, 11.9) = 31.3, p < 0.001; DH: F(2, 9.6) = 168.6, p < 0.001; VH: F(2, 13.4) = 697.7, p < 0.001.

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3. Fig. 2. Relative expression of glutamate transporter genes EAAT1 (Slc1a3), glutamine synthetase (Glul) and the protein of the connexin 43 (Gja1) family of slit contacts in the temporal cortex (TC), dorsal (DH) and ventral (VH) hippocampus of rats 7 days after epileptic status. * p < 0.05, ** p < 0.01, *** p < 0.001 in ANOVA with the a posteriori Tukey criterion or ANOVA with the Welch correction and the a posteriori Games–Howell criterion. Slc1a3: TC: F(2, 26) = 2.3, p = 0.12; DH: F(2, 23) = 11.3, p < 0.001; VH: F(2, 14.34) = 73.06, p < 0.001; Glul: TC: F(2, 25) = 1.36, p = 0.27; DH: F(2, 20) = 20.8, p < 0.001; VH: F(2, 16.25) = 33.56, p < 0.001; Gja1: TC: F(2, 12.65) = 9.47, p < 0.01; DH: F(2, 21) = 8.54, p < 0.01; VH: F(2, 29) = 41.8, p < 0.001.

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4. 3. Relative expression of genes of the main protein of Nlrp3 inflammasome, proinflammatory cytokine Il1b, anti-inflammatory cytokine Il1rn and pleiotropic cytokine Tgfb1 in the temporal cortex (TC), dorsal (DH) and ventral (VH) hippocampus of rats 7 days after epileptic status. * p < 0.05, ** p < 0.01, *** p < 0.001 in ANOVA with the a posteriori Tukey criterion or ANOVA with the Welch correction and the a posteriori Games–Howell criterion. Nlrp3: TC: F(2, 28) = 36.7, p < 0.001; DH: F(2, 21) = 66.1, p < 0.001; VH: F(2, 12.2) = 152.9, p < 0.001; Il1b: TC: F(2, 27) = 8.4, p < 0.01; DH: F(2, 19) = 13.85, p < 0.001; VH: F(2, 12.5) = 51.67, p < 0.001; Il1rn: TC: F(2, 28) = 10.46, p < 0.001; DH: F(2, 23) = 67.58, p < 0.001; VH: F(2, 13.97) = 326.4, p < 0.001.

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5. 4. Relative expression of astrocyte polarization marker genes: markers of A1 (Lcn2, Gbp2) and A2 (S100a10, Ptx3) states in the temporal cortex (TC), dorsal (DH) and ventral (VH) hippocampus of rats 7 days after epileptic status. * p < 0.05, ** p < 0.01, *** p < 0.001 in ANOVA with the a posteriori Tukey criterion or ANOVA with the Welch correction and the a posteriori Games–Howell criterion. Lcn2: TC: F(2, 24) = 14.82, p < 0.001; DH: F(2, 21) = 16.0, p < 0.001; VH: F(2, 15.45) = 89.87, p < 0.001; Gbp2: TC: F(2, 27) = 7.58, p < 0.01; DH: F(2, 22) = 17.37, p < 0.001; VH: F(2, 12.38) = 101.2, p < 0.001; S100a10: TC: F(2, 28) = 16.65, p < 0.001; DH: F(2, 10.25) = 22.68, p < 0.001; VH: F(2, 14.02) = 199.9, p < 0.001; Ptx3: TC: F(2, 13.88) = 17.65, p < 0.001; DH: F(2, 9.8) = 12.21, p < 0.01; VH: F(2, 26) = 25.74, p < 0.001.

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6. 5. Relative expression of microglial cell polarization marker genes: markers of M1 (Nos2) and M2 (Arg1) states in the temporal cortex (TC), dorsal (DH) and ventral (VH) hippocampus of rats 7 days after epileptic status. * p < 0.05, ** p < 0.01, *** p < 0.001 in ANOVA with the a posteriori Tukey criterion or ANOVA with the Welch correction and the a posteriori Games–Howell criterion. Nos2: TC: F(2, 28) = 11.07, p < 0.001; DH: F(2, 21) = 0.53, p = 0.596; VH: F(2, 23) = 0.063, p = 0.94; Arg1: TC: F(2, 13.96) = 5.183, p < 0.05; DH: F(2, 22) = 15.59, p < 0.001; VH: F(2, 28) = 1.322, p = 0.283.

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