1 / 11

TLR

TLR. M YD88 -D EPENDENT. M YD88 - I NDE PENDENT. TIR. TIR. TIR. TIR. Myd88. TRIF. TIRAP. TRAM. TRAF6. IRF3. (+ phosphorylation). I κ B α. P. NF- κ B. I κ B α. IRF3. NF- κ B. N UCLEAR T RANSLOCATION. I MMUNE R ESPONSE G ENES. T YPE I IFN. IRF3. NF- κ B. NF- κ B.

reed
Download Presentation

TLR

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. TLR MYD88-DEPENDENT MYD88-INDEPENDENT TIR TIR TIR TIR Myd88 TRIF TIRAP TRAM TRAF6 IRF3 (+ phosphorylation) IκBα P NF-κB IκBα IRF3 NF-κB NUCLEAR TRANSLOCATION IMMUNE RESPONSE GENES TYPE I IFN IRF3 NF-κB NF-κB

  2. Lee EG et al2000 Science: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Boone DL et al2004 Nat Immunol: The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Wertz IE et al2004 Nature: De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.

  3. host cells (e.g. APCs) ”sense” microbial contents in homeostasis • by TLRs and non-TLRs (e.g. NOD-like receptors) via binding to PAMPs Why do homeostatic TLR signals not trigger inflammation? How immune responses to commensal microflora are restrained during homeostasis? • quantity or strength of TLR signals • cell-type specific responses • cellular location of PAMP/TLR interactions • additional extra- or intracellular cues (regulator proteins e.g. A20)

  4. What is the role of the adaptor protein Myd88 in causing inflammation in A20-/- mice? → (i) Myd88 signals drive potent proinflammatory responses in the absence of A20 → (ii) A20 prevents recruitment of innate immune cells by restricting Myd88-dependent signals

  5. Do basal Myd88-dependent signals cause spontaneous activation and expansion of T cells in A20-/- mice? → Homeostatic Myd88-dependent signals cause T cell expansion and activation in the absence of A20

  6. Could the role of A20 involve signals on either HSCs or stromal cell? Or both? → Homeostatic Myd88 signals drive a broad spectrum of spontaneous proinflammatory pathways in the absence of A20 in HCs

  7. Does the commensal flora stimulate the homeostatic Myd88-dependent signals causing inflammation in A20-/- mice? Abx: vancomycin neomycin metronidazole ampicillin trimethoprim-sulfamethoxazole Ctrl: trimethoprim-sulfamethoxazole → Commensal bacteria drive spontaneous inflammation via Myd88 signals in the absence of A20

  8. How A20 regulates TRIF-dependent TLR responses? → (i) A20 is required for restricting acute – Myd88-independent – TRIF-dependent proinflammatory signals → (ii) Myd88- and IRF3-independent IFN-β production in the absence of A20

  9. TRAF6 as a physiological target for A20 during TLR signaling → A20 is essential for restricting TRAF6 ubiquitylation

  10. SUMMARY &DISCUSSION • Homeostatic TLR signals can in fact be inflammatory and rapidly lethal! ( ≤ BALANCE ≤ ) • A20 enzymatically regulates ubiquitylation of signaling proteins • (activity, stability, inhibiting further reactivation) • amplified effect by regulating other non-TLR signals, e.g. TNF • (but Myd88 dominance!) • intestinal bacteria are a major source of Myd88-dependent signals • role of A20 in epithelial cell function (mucosal DCs!)? • A20 restricts TRIF-dependent IFN responses by limiting TRIF-dependent NF-κB signaling • IL-10-/- with progressive colitis in 4-6 mo •  regulation of intestinal inflammation (STAT3) • A20-/- with widespread systemic inflammation in 3-6 wk •  regulation of systemic immune activation (TRAF6) IL-10 vs. A20

  11. TLR MYD88-DEPENDENT TIR TIR TIR TIR Myd88 TRIF MYD88-INDEPENDENT TIRAP TRAM A20 TRAF6 A20 IκBα P NF-κB IκBα NF-κB NUCLEAR TRANSLOCATION IMMUNE RESPONSE GENES TYPE I IFN NF-κB NF-κB

More Related