Abstract
TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca2+ mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.
Highlights
The innate immune system plays a crucial role in the inflammatory response to infection through the activity of receptors capable of recognizing defined molecular patterns present in a variety of microorganisms
Given that monocytes are the main TLR-expressing cell type in leukocytes [25], the main target for C5a in PBMCs, and that they orchestrate many of the TLRinduced responses of peripheral blood leukocytes, including those of neutrophils [25], we focused on monocyte C5a receptor (C5aR) and
These findings indicated that increased cell sensitivity to C5a following TLR activation is not due to C5aR upregulation
Summary
The innate immune system plays a crucial role in the inflammatory response to infection through the activity of receptors capable of recognizing defined molecular patterns present in a variety of microorganisms. The concerted activity of two components of the innate immune system, TLRs and complement, results in rapid inflammatory responses and orchestrates adaptive immune responses that lead to clearance of infection [1,2,3,4]. TLRs are critical to the triggering of the inflammatory response They recognize and respond to an array of microorganisms and their components, many of which can activate complement, by mediating a prompt and efficient proinflammatory response [1, 5]. This includes the production of a variety of inflammatory mediators, e.g. IL-6, TNF-a, IL-8
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