TLR8 Senses Staphylococcus aureus RNA in Human Primary Monocytes and Macrophages and Induces IFN-β Production via a TAK1–IKKβ–IRF5 Signaling Pathway

Abstract

Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus and elicits production of proinflammatory cytokines via MyD88–NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8–IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1–IKKβ–IRF5 pathway that can be inhibited by TLR2 signaling.

TLR8 Senses Bacterial RNA in Human Monocytes and Plays a Nonredundant Role for Recognition of Streptococcus pyogenes

“…5A, 5B). By contrast, cytochalasin D only partially suppressed cytokine production induced by S. aureus and L. monocytogenes, in line with the notion that TLR2 expressed on the cell surface has been implicated in sensing of both pathogens (30)(31)(32)(33)(34)(35) (Fig. 5C).…”

“…Residual activity observed in our experiments might be explained by incomplete silencing of TLR8 or may indicate the existence of additional, TLR8-independent recognition pathways. In a back-to-back manuscript with this study, Bergstrøm et al (35) further demonstrate that TLR8 was also critical for IFN-b induction by S. aureus, whereas TLR2 and TLR8 mediated redundant effects on pro-inflammatory cytokines including TNF and IL-1b.…”

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

“…With respect to TLR repertoire and function, humans are similar to cattle, which are widely accepted as the original host of GBS (37). It remains to be established whether TLR13 equips mice with specific resistance to bacteria or whether it takes over the role of TLR8, which was recently identified as a sensor for bacterial RNA in human myeloid cells (38)(39)(40). The latter seems likely, because mononuclear cells from mice and humans use the TLR signaling partners IRAK4 and MyD88 for the optimal response to streptococci and staphylococci (41).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 2)

“…Стимуляция лигандом Pam3CSK4 TLR2 человече-ских полиморфноядерных лейкоцитов индуцирует продукцию ряда цитокинов (IL-1β, IL-8/СХСL8, CCL3, CCL4, CCL20, CXCL-2 и CXCL1) [14,28]. Активация TLR2 Pam3CSK4 увеличивает экспрес-сию L-селектина и CD11b/CD18, участвующих в миграции нейтрофилов из кровеносного русла в ткань легкого, и приводит к усилению активности нейтрофильного фагоцитоза [7,16].…”

“…Согласно данным Bjarte Bergstrøm и соавт. [7], возбуждение одноцепочечной РНК бактерий Staphylococcus aureus рецептора TLR8 макрофагов и моноцитов активи-рует TAK1-зависимые и TAK1-независимые вну-триклеточные сигнальные пути. Активация TAK1-зависимого пути инициирует фактор транскрипции IRF5, что приводит к продукции IFN-β и IL-12, в то время как возбуждение TAK1-независимого сиг-нального пути активирует транслокацию фактора транскрипции NF-κB в ядро клетки с последующей продукцией провоспалительных цитокинов (IL-1β и IL-18).…”