The Toll-like receptor 4-activated neuroprotective microglia subpopulation survives via granulocyte macrophage colony-stimulating factor and JAK2/STAT5 signaling

Mayumi Kamigaki; Izumi Hide; Yuhki Yanase; Hiroko Shiraki; Kana Harada; Yoshiki Tanaka; Takahiro Seki; Toshihiko Shirafuji; Shigeru Tanaka; Michihiro Hide; Norio Sakai

doi:10.1016/j.neuint.2016.01.003

The Toll-like receptor 4-activated neuroprotective microglia subpopulation survives via granulocyte macrophage colony-stimulating factor and JAK2/STAT5 signaling

Neurochem Int. 2016 Feb:93:82-94. doi: 10.1016/j.neuint.2016.01.003. Epub 2016 Jan 21.

Authors

Affiliations

¹ Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
² Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan. Electronic address: ihide@hiroshima-u.ac.jp.
³ Department of Dermatology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

PMID: 26802935
DOI: 10.1016/j.neuint.2016.01.003

Abstract

Toll-like receptor (TLR) 4 mediates inflammation and is also known to trigger apoptosis in microglia. Our time-lapse observations showed that lipopolysaccharide (LPS) stimulation induced rapid death in primary cultures of rat microglia, while a portion of the microglia escaped from death and survived for much longer than 2 days, in which time, all of the control cells had died. However, it remains unclear how the LPS-stimulated microglia subpopulation could continue to survive in the absence of any supplied growth factors. In the present study, to clarify the mechanism underlying the LPS-stimulated survival, we investigated whether microglia could produce their own survival factors in response to LPS, focusing on macrophage colony-stimulating factor (M-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-34, which are mainly supplied by astrocytes or neurons. The LPS-stimulated microglia drastically induced the expression of the GM-CSF mRNA and protein, while M-CSF and IL-34 levels were unchanged. The surviving microglia also significantly upregulated the expression of GM-CSF receptor (GM-CSFR) mRNA without affecting M-CSFR. As for the GM-CSFR downstream signal, LPS resulted in the phosphorylation of STAT5 and its translocation to the nucleus in the surviving microglia. Moreover, a specific JAK2 inhibitor, NVP-BSK805, suppressed STAT5 phosphorylation and microglia survival in response to LPS, indicating a critical role of the JAK2/STAT5 pathway in this survival mechanism. Together, these results suggest that a subpopulation of TLR4-activated microglia may survive by producing GM-CSF and up-regulating GM-CSFR. This autocrine GM-CSF pathway may activate the JAK2/STAT5 signaling pathway, which controls the transcription of survival-related genes. Finally, these surviving microglia may have neuroprotective functions because the neurons remained viable in co-cultures with these microglia.

Keywords: GM-CSF; LPS; Microglia; Neuroprotection; Survival; TLR4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
Janus Kinase 2 / metabolism*
Microglia / metabolism*
Rats
Rats, Wistar
STAT5 Transcription Factor / metabolism*
Toll-Like Receptor 4 / physiology*

Substances

STAT5 Transcription Factor
Stat5a protein, rat
Toll-Like Receptor 4
Granulocyte-Macrophage Colony-Stimulating Factor
Jak2 protein, rat
Janus Kinase 2