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. Author manuscript; available in PMC: 2020 Sep 25.
Published in final edited form as: Cell Rep. 2020 Sep 8;32(10):108100. doi: 10.1016/j.celrep.2020.108100

Figure 7. Proposed Mechanisms Whereby Enteric Glia Regulate Visceral Pain through M-CSF Signaling with Macrophages.

Figure 7.

Schematic illustrating signaling mechanisms between enteric glia and macrophages identified in this study. Proinflammatory stimuli such as IL-1β induce glial reactivity and signaling through connexin-43 (Cx43) hemichannels. Cx43 hemichannels mediate calcium (Ca2+) responses in enteric glia (McClain et al., 2014). Glial activity increases signaling through protein kinase C (PKC) and activates tumor necrosis factor α converting enzyme (TACE), possibly via mitogen-activated protein kinase (MAPK) (Horiuchi and Toyama, 2008). Glial Cx43-dependent TACE activation results in proteolytic cleavage of cell membrane M-CSF (mM-CSF), increased release of soluble M-CSF (sM-CSF), and, in turn, macrophage activation. M-CSF produced by neurons and interstitial cells of Cajal could also contribute to macrophage activation. Data shown in this study provide evidence that interactions between enteric glia and macrophages contribute to the development of persistent hypersensitivity of visceral afferents in the intestines.