Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection

Dutta, Kallol; Mishra, Manoj Kumar; Nazmi, Arshed; Kumawat, Kanhaiya Lal; Basu, Anirban

doi:10.1016/j.imbio.2009.12.003

Cited by 47 publications

(52 citation statements)

References 46 publications

(42 reference statements)

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“…Mishra et al [65] reported a reduction of MMP-9 activity following minocycline administration in JEV-infected mice that may be as a result of microglial inhibition. Recently, Dutta et al [69] investigated that minocycline reduces proinflammatory cytokine levels, ROS levels, and stress protein expression that are increased after JEV infection, modulates levels of intracellular signaling molecules and transcription factors that are related to cell survival, and modulates the vascular endothelial growth factor (VEGF)-MMP pathway within macrophages following JEV infection. MMP-9 activity has also been found to decrease in culture supernatants of JEV-infected and minocycline-treated cells as compared to only JEV-infected and mock-infected by zymography [69].…”

Section: Discussionmentioning

confidence: 99%

Upregulated Expression of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases in BALB/c Mouse Brain Challenged with Japanese Encephalitis Virus

Shukla

Shakya²,

Tn³

et al. 2012

Neuroimmunomodulation

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Background: Uncontrolled immune responses in the nervous system are potentially damaging following Japanese encephalitis virus (JEV) infection. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) act together to control the proteolysis of extracellular matrix. Disbalances in the MMP/TIMP system during virally induced neurodegenerative processes and inflammations are responsive to changes in the progression of diseases. Methods: The expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-3 in JEV-infected mouse brain was analyzed by RT-PCR for semiquantitation and ELISA for estimation of protein along with brain histopathology at different days postinoculation (dpi). Gelatin gel zymography was performed for MMP-2 and MMP-9 activities. Results: In the virus-infected group, expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-3 was found to be increased from 1 dpi to 6 dpi as compared to controls by both RT-PCR and ELISA. The expressions of MMPs and TIMPs at mRNA and protein levels were in concordance with each other. Post hoc multiple comparison analysis between days revealed that, in the virus-infected groups, significant increases (p < 0.05) in MMP and TIMP levels were observed between various dpi at both mRNA and protein levels. Only the MMP-7 protein level at 6 dpi was not significant compared to 5 dpi (p = 0.99). Conclusion: Overexpression of MMPs and TIMPs is associated with disease severity in the central nervous system (CNS) during JEV infection. Our results showed that JEV infection can alter the expression of MMPs and TIMPs in the CNS. Thus, assessing these important immune mediators in CNS infection appears to play an important role in the development of symptoms and may help to understand the JEV-induced neurological disorders. More studies are required on this important enzymatic system to study their role in immune mediated pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Upregulated Expression of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases in BALB/c Mouse Brain Challenged with Japanese Encephalitis Virus

Shukla

Shakya²,

Tn³

et al. 2012

Neuroimmunomodulation

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“…This observation is significant as we believe that these cells are possibly involved in the viral transport from the periphery to the CNS. In another study we have seen that JEV infects and persists within macrophages without causing cell death for at least 72 h (Dutta et al 2010) and others have shown this time to be extendable up to 6 weeks (Aleyas et al 2009). Thus, it may be possible that minocycline, by preventing migration or accumulation of cells of monocyte/macrophage lineage in the lymph node, is depriving the virus of carriers to the CNS.…”

Section: Discussionmentioning

confidence: 85%

Minocycline Differentially Modulates Viral Infection and Persistence in an Experimental Model of Japanese Encephalitis

Dutta

Kumawat

Nazmi

et al. 2010

J Neuroimmune Pharmacol

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Japanese encephalitis (JE) is caused by a neurotropic flavivirus that causes CNS damage that leads to death in acute cases or permanent neuropsychiatric sequel in survivors. The course of infection of this virus is not well defined though it is clear that it evades the host's innate immune response in the periphery. The current study was designed to investigate the time-dependent changes in the spleen and lymph node, apart from the CNS that are infected by the Japanese encephalitis virus (JEV). Our previous studies have led to the identification of minocycline, a semi-synthetic antibiotic, as a protective drug in JE. In this study we have also investigated the role of minocycline on the peripheral organs that are infected by JEV. Levels of IL-12 and MCP-1 in the organs were estimated by cytometric bead array, and immunohistochemical studies were performed on cryosections of tissue to detect CD3- or CD11b-positive cells as well as JEV antigen. We found that the levels of T cell-activating cytokine IL-12 and MCP-1 levels were significantly elevated in JEV-infected tissue samples in a time-dependent manner. Corresponding to this increase was the increase in the number of CD3- and CD11b-positive cells in the tissues of infected animals. Minocycline treatment abrogated these changes. Minocycline treatment also resulted in the gradual decrease in the number of CD11b (but not CD3) positive cells in the lymph node and spleen, even though the virus persisted in these organs. We also observed structural changes in the spleen following minocycline treatment.

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“…The fluid was then centrifuged at 1,200 rpm, the supernatant discarded, and the pellet was resuspended in 3 ml of 10% RPMI-FBS. The number of viable cells was estimated by trypan blue dye exclusion technique (Dutta et al 2010b). …”

Section: Isolation Of Macrophagesmentioning

confidence: 99%

“…The level of ROS produced within cells of the control and each treatment groups was measured by the cell-permeable, non-polar, H 2 O 2 -sensitive probe 5 (and 6)-chlromethyl-20,70-dichlorodihydrofluoresceindiacetate (CM-H 2 DCFDA; Sigma) by the method described previously (Dutta et al 2010b). Briefly, macrophages were plated in five 90 mm plates at a density of 4×10 5 cells/ml (after triplicate counts with a haemocytometer) and were treated as described above.…”

Section: Measurement Of Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…However, it is not known whether this is true for other neurotropic viruses. Studies have shown that cells of monocyte/macrophage lineage harbor JEV (Mathur et al 1988;Aleyas et al 2009;Dutta et al 2010b) for significantly longer time periods as compared to other cells (Yang et al 2004) and possibly serve as 'Trojan Horses' that may carry the virus to the CNS (Diamond 2003). Neuronal death in JE has till date been attributed to exacerbated inflammatory responses due to microglial activation.…”

Section: Introductionmentioning

confidence: 99%

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Japanese Encephalitis Virus-Infected Macrophages Induce Neuronal Death

Nazmi

Dutta

Das

et al. 2011

J Neuroimmune Pharmacol

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Inflammation in the central nervous system (CNS) in Japanese encephalitis (JE) is shown to be the result of microglial activation that leads to the release of various proinflammatory mediators. Peripheral macrophages have been reported to infiltrate into the CNS in JE, though their contribution to the inflammatory process is yet to be elucidated. In this study, using an in vitro macrophage model, we have shown that upon JE virus infection, these cells secrete various soluble factors which may significantly add to the existing inflammatory milieu and lead to apoptotic or necrotic death of neurons. However, it is difficult to quantify the extent of involvement of either the microglia or infiltrating macrophages in the inflammatory processes.

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Minocycline differentially modulates macrophage mediated peripheral immune response following Japanese encephalitis virus infection

Cited by 47 publications

References 46 publications

Upregulated Expression of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases in BALB/c Mouse Brain Challenged with Japanese Encephalitis Virus

Upregulated Expression of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases in BALB/c Mouse Brain Challenged with Japanese Encephalitis Virus

Minocycline Differentially Modulates Viral Infection and Persistence in an Experimental Model of Japanese Encephalitis

Japanese Encephalitis Virus-Infected Macrophages Induce Neuronal Death

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