Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens

Lech, Maciej; Kulkarni, Onkar P.; Pfeiffer, Stephanie; Savarese, Emina; Krug, Anne; Garlanda, Cecília; Mantovani, Alberto; Anders, Hans‐Joachim

doi:10.1084/jem.20072646081408c

Cited by 13 publications

(18 citation statements)

References 6 publications

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“…Mice genetically deficient for A20 develop severe systemic inflammation, cachexia, and succumb to an early death, a process alleviated in the absence of MyD88 or upon deletion of the intestinal flora with broad-spectrum antibiotics (11). Another TLR regulator, SIGIRR, regulates intestinal inflammation and susceptibility to DSSinduced colitis (40), as well as regulating susceptibility to lupus (41). Control of inflammatory cytokines is critical for regulation of systemic inflammation, as well as shaping the adaptive immune response.…”

Section: Discussionmentioning

confidence: 99%

Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt

Troutman

Fulenchek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

154

180

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Toll like receptors (TLRs) use Toll-IL-1 receptor (TIR) domain-containing adapters, such as myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adapter inducing IFN-β (TRIF), to induce activation of transcription factors, including NF-κB, MAP kinases, and IFN regulatory factors. TLR signaling also leads to activation of PI3K, but the molecular mechanism is not understood. Here we have discovered a unique role for B-cell adapter for PI3K (BCAP) in the TLR-signaling pathway. We find that BCAP has a functional N-terminal TIR homology domain and links TLR signaling to activation of PI3K. In addition, BCAP negatively regulates proinflammatory cytokine secretion upon TLR stimulation. In vivo, the absence of BCAP leads to exaggerated recruitment of inflammatory myeloid cells following infections and enhanced susceptibility to dextran sulfate sodium-induced colitis. Our results demonstrate that BCAP is a unique TIR domaincontaining TLR signaling adapter crucial for linking TLRs to PI3K activation and regulating the inflammatory response.inflammation | negative regulator | macrophage | innate immunity | pattern recognition receptors

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Section: Discussionmentioning

confidence: 99%

Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt

Troutman

Fulenchek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

154

180

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“…Sigirr in B6 lpr/lpr mice (which develop very mild lupus erythematosus) resulted in development of severe disease characterized by evidence of significant inflammation (Lech et al, 2007) and production of proinflammatory mediators (Lech et al, 2008). Similarly post-ischaemic renal failure was worse in SIGIRR-deficient mice and this was accompanied by significant leukocyte transmigration in the microvasculature (Lech et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

SIGIRR modulates the inflammatory response in the brain

Watson

Costello

Carney

et al. 2010

Brain, Behavior, and Immunity

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One of the more recently described members of the interleukin-1 (IL-1) receptor family, single-Ig-Interleukin-1 related receptor (SIGIRR), has been identified as a negative regulator of inflammation in several tissues. It modulates the responses triggered by stimulation of Toll-like receptor (TLR) 4 and IL-1 in several peripheral cell types, possibly in an NFκB-dependent manner. Consistently, responses to lipopolysaccharide (LPS) are exaggerated in SIGIRR-deficient mice and the symptoms of experimental inflammatory conditions are more profound in these animals. Here we set out to establish whether the absence of SIGIRR was associated with inflammatory changes in the brain and report that, LPS induced a greater effect on CD40 and ICAM mRNA in mixed glia prepared from SIGIRR -/-, compared with wildtype mice. This was associated with parallel changes in TNFα and IL-6 at mRNA and protein levels, an effect which was observed in purified microglia but not astrocytes. Similarly, LPS exerted a more profound effect on microglial activation and cytokine production in hippocampal tissue prepared from SIGIRR -/-, compared with wildtype mice. The effect of LPS on exploratory behaviour was also accentuated in SIGIRR -/-mice. The evidence suggests that these changes are a likely consequence of increased hippocampal expression of CD14 and TLR4, and NFκB activation in SIGIRR -/-mice.

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“…Factors like single-immunoglobulin IL-1 receptorrelated protein (SIGIRR) usually suppress TLR signaling in antigen presenting cells by interfering with the intracellular Toll-IL-1 receptor (TIR) domain interactions. Data from our laboratory showed that Sigirr-deficient C57BL/6lpr/lpr mice develop a severe lymphoproliferative syndrome, multiple RNA-and DNAspecific autoantibodies and diffuse proliferative lupus nephritis and pneumonitis, which is absent in age-matched C57BL/6lpr/lpr mice [19]. Thus, under normal conditions, Tlr7 signaling is actively suppressed to prevent inappropriate RNA autoantigen recognition.…”

Section: See Accompanying Article By Fairhurst Et Almentioning

confidence: 95%

Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

2008

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Toll-like receptors (TLR), such as TLR7, were first described as innate pathogen recognition receptors that trigger appropriate antimircrobial immune responses upon exposure to pathogen-associated molecules, e.g. viral ssRNA. In parallel to ongoing studies on TLRbiology, mounting experimental evidence suggests that endogenous RNA-related autoantigens may also activate dendritic cells (DC) and B cells through TLR7. TLR7-mediated DC activation, autoantibody secretion, lymphoproliferation, and autoimmune tissue injury, are frequently observed in various murine models of systemic lupus and lupus nephritis. A paper in the current issue of the European Journal of Immunology, provide striking experimental evidence for this concept; the authors show that the Y chromosome-linked autoimmune accelerating (Yaa) translocation from the X-chromosome, consisting of 16 genes including Tlr7, largely mediates the autoimmune phenotype via the duplication of Tlr7. This finding highlights the need to address the significance of TLR7 in human lupus in terms of both genetic risk and as a therapeutic option.

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Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens

Cited by 13 publications

References 6 publications

Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt

Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt

SIGIRR modulates the inflammatory response in the brain

Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

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