Fig. 7

Proposed model of FGFR activation pathways in response to live B. burgdorferi exposure (a) and intersectionality of the induced and downregulated FGFs with other neurological conditions (b). a Exposure of primary rhesus microglia to live B. burgdorferi upregulates the surface expression of FGFR1, FGFR2 and FGFR3 [1]. Host–pathogen interaction also induces expression of several FGFs such as FGF6, FGF10, FGF12, and FGF23, of which FGF6 (and likely FGF10 and FGF23) are secreted from the cells [2]. Whether FGF12 is secreted extracellularly is unclear. Ligand binding of FGF6 to FGFR1 induces phosphorylation of the receptor [3] and secretion of IL-6 and CXCL8. The intracellular signaling pathway is likely through MAPK pathways, particularly ERK, as have been demonstrated in our previous study in primary rhesus microglia [22]. While FGF6 was shown to activate FGFR1 in this study, it can also activate other FGFRs. Similarly, FGF10, shown to activate FGFR2 in the model, can also activate FGFR1, while FGF23 can activate FGFR3, FGFR2 and FGFR1 [86]. As FGF6, 10 and 12 only activated IL-6 and/or CXCL8, but the inhibition of FGFR1 individually by siRNA downregulated IL-6, CXCL8 as well as CCL2, it is likely that other than FGF23, non-FGF molecules present in the supernatant also likely activate this receptor. It should be noted that only autocrine effects of FGF binding FGFRs in microglia are shown. It is possible that some paracrine effects on other glial cells also occur and will be tested in future studies. Finally, our study also demonstrated that synthesis (or inhibition) of FGFs (except for FGF8, 23, and 16 & 21 to an extent) was also through FGFR1 (Additional file 1: SM4), as suppression of FGFR1 signaling with PD166866 modulated FGF levels [4]. b shows the known neurological roles of the FGFs from this study and others. [−] indicates (putative) negative roles, while [+] indicates (putative) positive effects of the indicated FGFs. The listed roles are not exhaustive. Please see the Discussion section for details. Upregulation of FGFs with deleterious effects, and downregulation of FGFs with ameliorative effects can contribute towards Lyme neuroborreliosis sequelae and other neuropathologies. Both figures created with BioRender.com