Figure 7

Proposed model of signaling pathways activated in primary NHP microglia in response to B. burgdorferi. Upon contact with the bacterium, the microglial TLR2 and TLR5, respectively, sense B. burgdorferi lipoproteins and flagella (likely exposed by fragmented or by phagocytosed bacteria), initiating downstream responses by recruitment of adaptor molecules such as MyD88. Whether signaling is initiated both at the surface and in the intracellular compartments or exclusively through the latter is not clear, neither is the mechanism of TLR2/5 internalization. However, once signaling is initiated, further downstream signaling leads to activation of MAPK pathways, mainly the ERK pathway, leading to production of inflammatory mediators. Upregulation of TLR4 has been detected by confocal microscopy, perhaps through a lipooligosaccharide moiety or as a result of concomitant activation along with other TLRs. Its role in inflammation is unclear and neither is its intracellular localization (hence the question mark in the corresponding arrow). Signaling through intracellular NOD2, mediated by MDP molecules in phagocytosed bacteria, leads to anti-inflammatory effects, especially for CCL2 and perhaps other mediators. Thus, the overall inflammatory outcome in microglia in response to B. burgdorferi is likely through the positive and negative regulation of several key signaling pathways. Thickness of the downstream signaling lines depicts signal strength. Arrowheads indicate induction, and horizontal bars at the end of the lines indicate inhibition. Dashed lines show additional possible inhibitory signals. Dotted lines indicate internalization either through phagocytosis or endocytosis, with phagosome and/or endosome in open ovals. Dashed and dotted lines indicate unclear processes. CCL2, chemokine (C-C) motif ligand 2; CXCL8, chemokine (C-X-C) motif ligand 8; ERK, extracellular signal-regulated kinase; IL-6, interleukin 6; JNK, Jun N-terminal kinase; MDP, muramyl dipeptide; MyD88, myeloid differentiation primary response 88; NOD2, nucleotide-binding oligomerization domain containing 2; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRIF, Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β.