Crosstalk pathways between Toll-like receptors and the complement system

Abstract

The Toll-like receptors (TLRs) and complement are key innate defense systems that are triggered rapidly upon infection. Although both systems have been investigated primarily as separate entities, an emerging body of evidence indicates extensive crosstalk between complement and TLR signaling pathways. Analysis of these data suggests that the complement-TLR interplay reinforces innate immunity or regulates excessive inflammation, through synergistic or antagonistic interactions, respectively. However, the facility of complement and TLRs for communication is exploited by certain pathogens as a means to modify the host response in ways that favor the persistence of the pathogens. Further elucidation of regulatory links between complement and TLRs is essential for understanding their complex roles in health and disease.

Figure 1

Complement regulation of TLR-induced cytokines of the IL-12 family. Activation of these complement receptors by their natural ligands downregulates TLR-induced mRNA expression of IL-12p35, IL-12/IL-23p40, IL-23p19 and IL-27p28 and production of bioactive IL-12, IL-23 and IL-27 [9,11,15,16,41,53]. The underlying signaling mechanisms involve induction of PI3K or ERK1/2 signaling, which in turn suppresses crucial transcription factors (IRF-1 and IRF-8), although the CD46 mechanism appears to be exerted at the post-transcriptional level. However, these receptors can also be activated by bacterial or viral pathogens, which thereby can manipulate TLR-induced IL-12 cytokines and associated T-helper responses in ways that interfere with protective immunity [35,41,53]. Although C5aR cannot be directly activated by pathogens, C5aR can come under pathogen control through microbial C5 convertase-like enzymes, which generate biologically active C5a [34]. The regulatory mechanisms shown appear to be cell-type specific and have been documented in human or mouse monocytes–macrophages. Figure I. TLRs and their major ligands. Figure I. Simplified representation of the complement cascade.

Figure 2

TLR–CR3 crosstalk pathways. Induction of TLR2 inside-out signaling, mediated by Rac-1, PI3K and cytohesin-1 (Cyt-1), upregulates the high-affinity state of CR3. The terminal component, Cyt-1, contains a pleckstrin homology (PH) domain, which binds and uses phosphatidylinositol-(3,4,5)-triphosphate (PIP3) as a docking site to interact (via its Sec7 domain) with the CD18 cytoplasmic tail of CR3. Certain bacteria (P. gingivalis, M. tuberculosis, B. anthracis) bind CD14 and induce TLR2 inside-out signaling for activating and binding macrophage CR3, which leads to relatively safe uptake of these organisms, thus enhancing their intracellular persistence [13,34,46,47]. In a reciprocal manner, CR3 can regulate the signaling activity of TLRs that utilize TIRAP as an adaptor, i.e. TLR2 and TLR4 [49]. Specifically, outside-in signaling by CR3 leads to activation of ADP ribosylation factor 6 (ARF6) and induction of phosphatidylinositol-(4,5)-bisphosphate (PIP2) production by phosphatidylinositol 5-kinase (PI5K). This activity promotes the targeting of TIRAP to membrane-bound PIP2 through its PIP2-binding domain. TIRAP subsequently acts as a sorting adaptor, which facilitates the recruitment of the signaling adaptor MyD88 to either TLR2 or TLR4 for initiation of downstream signaling [49].