TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17

Abstract

TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF-driven inflammatory pain and for initiation of GM-CSF-driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF→CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated.

GM-CSF in inflammation

“…CCL17 may not necessarily be acting as a T cell chemokine in its control of inflammation and its associated pain; i.e., it appears that CCL17 has other, hitherto undefined, functions (Weber et al, 2011;Heiseke et al, 2012;Cook et al, 2018b;Lee et al, 2018). In this connection CCL17-driven inflammatory pain is cyclooxygenase 2 dependent, suggesting eicosanoid involvement ( Fig.…”

“…GM-CSF-IRF4 signaling can in addition control expression in monocytes and macrophages of other potential proinflammatory effectors, such as surface-bound MHC class II. GM-CSF and TNF, potentially produced by numerous cell types (not shown) in response to various stimuli, including damage-associated molecular patterns (DAMPs), can engage in a cytokine loop, thus potentially linking TNF biology to the GM-CSF-CCL17 pathway (Cook et al, 2018b). critical effector cytokine produced by IL-23-stimulated Th17 cells in mice, leading to the concept that GM-CSF is a Th17related cytokine (Sonderegger et al, 2008;Codarri et al, 2011;El-Behi et al, 2011;Hamilton et al, 2017); however, it has been put forward that a novel subset of Th cells (Th-GM) predominantly produces GM-CSF but not IL-17 and is essential for EAE development (Sheng et al, 2014;Komuczki et al, 2019), and IL-12-polarized Th1 cells produce GM-CSF and induce EAE independently of IL-23 (Carbajal et al, 2015;Grifka-Walk et al, 2015).…”

The Role of Granulocyte-Macrophage Colony-Stimulating Factor in Murine Models of Multiple Sclerosis

“…GM-CSF is known to play an indispensable role of JAK2-STAT5 signaling [19]. GM-CSF can also activate the interferon regulatory factor 4 (IRF4)-CCL17 pathway which is associated with pain [20]. GM-CSF signaling activates IRF4 by enhancing the activity of JMJD3 demethylase [20].…”

“…GM-CSF can also activate the interferon regulatory factor 4 (IRF4)-CCL17 pathway which is associated with pain [20]. GM-CSF signaling activates IRF4 by enhancing the activity of JMJD3 demethylase [20]. The upregulation of IRF4 results in an increased expression of MHC II by differentiating monocytes and an increase in the production of CCL17 [20].…”

“…GM-CSF signaling activates IRF4 by enhancing the activity of JMJD3 demethylase [20]. The upregulation of IRF4 results in an increased expression of MHC II by differentiating monocytes and an increase in the production of CCL17 [20]. Additionally, GM-CSF signaling is implicated in the AKT-ERK mediated activation of NF-κB [21].…”