Table 1.

Crosstalk between complement and Toll-like receptor signaling pathways

Receptors involved		Outcomes	Possible crosstalk point(s)	Experimental system	Refs
Complement	TLRs
C3aRa	TLR2	Enhanced TNF-α, IL-1β and IL-6 responses; lower IL-12 and IL-23	MAPK (ERK1/2, JNK) and PI3K	Mouse macrophages, human monocytes, in vivo mouse models	[5,9,11,16]
C5aR	TLR4
	TLR9	Inhibition of Th1; promotion of Th17
Receptors downstream of C3 (C5aR and perhaps C3aR)	CD14/TLR4	Enhanced induction of oxidative burst, proinflammatory cytokines (TNF-α, IL-1β, IL-8), antimicrobial responses, phagocytosis and killing of E. coli	Not addressed	Human whole-blood model	[10]
Receptors of and downstream of C3 (C3aR, C5aR, CR3)	TLR9	Enhanced expression of activation/maturation markers (CD40, CD83) and cytokines (TNF-α, IL-6, IL-8) in antigen-presenting cells	Not addressed	Human whole-blood model	[12]
		CpG ODN-induced complement activation leading to enhanced CR3 uptake of CpG ODN
C5aR	TLR2	Synergistic induction of cAMP and suppression of nitric oxide-dependent bacterial killing	Adenylate cyclase	Mouse macrophages, in vivo mouse model	[19]
C3aR	TLR4	Increased IL-12 and IL-23 production	ERK1/2	Human or mouse dendritic cells, in vivo mouse model	[41,57,59]
C5aR
CR3	TLR2	Selective inhibition of IL-12; other proinflammatory cytokines unaltered or enhanced	ERK1/2	Human monocytes, mouse macrophages, in vivo mouse models	[41,53,54]
	TLR4
CR3	TLR2	TIRAP recruitment to activated TLRs	PIP2	Mouse macrophages	[49]
	TLR4
CR3	TLR2	Activation of the CR3 ligand-binding capacity via TLR2 inside-out signaling	Rac1, PI3K and cytohesin-1	Human monocytes or neutrophils, mouse macrophages	[8,46,47]
C5L2b	TLR4	Enhanced HMGB1 induction	MAPK (MEK1/2 and JNK1/2) and PI3K/Akt	Mouse macrophages, cecal ligation and puncture-induced sepsis model in mice	[14]
C5L2	TLR4	Inhibition of TNF-α; enhancement of IL-6 and CR3 (Mac-1) expression	MAPK (ERK1/2, JNK, p38)	Mouse neutrophils	[26]
C5L2	TLR4	Suppressed induction of TNF-α, IL-6 and CD86	ERK1/2 and Akt	Mouse macrophages	[26]
gC1qR	TLR4	Selective suppression of IL-12	PI3K	Human monocytes and dendritic cells	[15,35 ]
cC1qR	TLR4	Enhanced expression of co-stimulatory molecules, TNF-α, IL-12, and promotion of Th1 (no evidence for cC1qR–TLR4 synergy, possible additive effects)	NF-κB	Human dendritic cells	[63]
Unspecified C1q/MBL receptor	TLR4	Inhibition of IL-1β and TNF-α and enhancement of IL-10	CREB and NF-κB	Human monocytes (also macrophages and dendritic cells but without effect on IL-10)	[6,37]
CD46	TLR4	Selective suppression of IL-12	Post-transcriptional mechanism	Human monocytes–macrophages	[41,42]
CD46	TLR4	Enhanced expression of IL-12p35, IL-23p19 and IL-12/IL-23p40 Promotion of Th17	Not addressed	Human dendritic cells	[62]

^aC5aR considerably more potent than C3aR in regulating TLR-induced cytokine responses; C3aR not involved in Th17 development.

^bAn alternative to C5L2–TLR4 crosstalk is that C5L2 might be required for optimal TLR4 signaling (e.g. co-receptor function).