Abstract
The release of endogenous molecules from the skin after injury has been proposed to influence inflammation. Recent studies have found that pro-inflammatory signals can be generated by damaged endogenous self-RNA, and this event is detected by TLR3. Conversely, release of endogenous fragments of hyaluronic acid (HA) after injury has been proposed to inhibit LPS induced inflammation driven by TLR4. In this study we investigated if HA oligomers could also influence inflammation mediated by TLR3. A tetramer form of HA (oligo-HA) was added to MH-S cells (mouse alveolar macrophage cell line) that were then activated by poly(I:C). ELISA analysis of culture supernatants showed that the presence of oligo-HA suppressed the poly(I:C) induced release of IL-6 and TNFα. IL-6 mRNA expression was also suppressed as measured by quantitative RT-PCR. To determine the mechanism of action for oligo-HA to inhibit poly(I:C), macrophages derived from wild-type (WT), Tlr2−/− or Tlr4−/− mice were treated with oligo-HA and poly(I:C). Similar to WT cells, Tlr2−/− macrophages were inhibited by oligo-HA and retained suppression of cytokine release. In contrast, Tlr4−/− macrophages lost the capacity to be suppressed by oligo-HA. An increase in Traf1 (TLR negative regulator) mRNA was observed after oligo-HA treatment of WT but not in Tlr4−/− macrophages, and oligo-HA did not suppress cytokine responsiveness in Traf1−/− macrophages. These results show that oligo-HA acts through TLR4 and TRAF1 to inhibit TLR3-dependent inflammation. This observation illustrates the complex immunomodulatory action of endogenous products released after injury.
Highlights
Immediate defense against pathogen invasion depends on pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to identify the presence of danger from microbial invasion [1]
Oligo-hyaluronic acid (HA) treatment of macrophages from Tlr22/2 mice showed suppression similar to macrophages from WT mice (Figure 3C). These results indicated that the suppression of poly(I:C)-induced cytokine release by oligoHA was dependent on TLR4, but not TLR2
These results indicated that oligo-HA treatment could induce these negative regulators of TLR3 in macrophages
Summary
Immediate defense against pathogen invasion depends on pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to identify the presence of danger from microbial invasion [1]. This system was thought to function exclusively to recognize pathogens. Release of RNA has been shown to trigger inflammation after injury and is dependent on recognition by TLR3 [3,4] It is currently unclear how these multiple molecules interact with microbial products present in the complex environment of the wound, but several studies have suggested that the interplay between host and microbial-derived molecules serves to modulate the repair process and influences wound repair [5]
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