Cutting Edge: AIM2 and Endosomal TLRs Differentially Regulate Arthritis and Autoantibody Production in DNase II–Deficient Mice

Baum, Rebecca; Sharma, Shrutie; Carpenter, Susan; Li, Quan-Zhen; Busto, Patricia; Fitzgerald, Katherine A.; Marshak‐Rothstein, Ann; Gravallese, Ellen M.

doi:10.4049/jimmunol.1402573

Cited by 88 publications

(100 citation statements)

References 18 publications

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“…In this disease, scavenging of DNA by the antimicrobial cathelicidin peptide LL-37 reduced IL-1β secretion, suggesting that extracellular DNA (possibly of self-origin) could act as a danger signal. Similarly, in arthritis models driven by deficiency of the lysosomal endonuclease DNase2, the impaired ability of macrophages to degrade self-DNA released by damaged tissues triggers an inflammatory syndrome that is partially AIM2-dependent (49,50).…”

Section: Discussionmentioning

confidence: 99%

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Micco

Frera

Lugrin

et al. 2016

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

104

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Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavirmediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.inflammasome | nuclear envelope stress | DNA sensors | zmpste24 | Nelfinavir

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Section: Discussionmentioning

confidence: 99%

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Micco

Frera

Lugrin

et al. 2016

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

104

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“…Prior studies have also shown that DKO mice can make anti-DNA autoantibodies (2), and implicated STING in DNA autoantibody production. Nevertheless, our own autoantigen array data has shown that DKO mice make antibodies against an extensive panel of nuclear autoantigens, and that autoantibody production, even in this model, is TLR-dependent (12). The current study was undertaken to gain a better understanding of DKO autoantibody specificities and the role of endosomal and cytosolic nucleic acid sensors in DKO autoantibody production.…”

Section: Introductionmentioning

confidence: 99%

Cutting Edge: DNase II Deficiency Prevents Activation of Autoreactive B Cells by Double-Stranded DNA Endogenous Ligands

Pawaria

Moody

Busto

et al. 2015

The Journal of Immunology

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In mice that fail to express the phagolysosomal endonuclease, DNase II, and the type I IFN receptor, excessive accrual of undegraded DNA results in a STING-dependent, TLR-independent inflammatory arthritis. These double knockout (DKO) mice develop additional indications of systemic autoimmunity, including anti-nuclear autoantibodies and splenomegaly, not found in Unc93b1−/− DKO mice and therefore TLR-dependent. The DKO autoantibodies predominantly detect RNA-associated autoantigens, commonly targeted in TLR7-dominated SLE-prone mice. To determine whether an inability of TLR9 to detect endogenous DNA could explain the absence of dsDNA-reactive autoantibodies in DKO mice, we used a novel class of bifunctional autoantibodies, IgM/DNA DVD-Ig™ molecules, to activate B cells through a BCR/TLR9-dependent mechanism. DKO B cells could not respond to the IgM/DNA DVD-Ig™ molecule, despite a normal response to both anti-IgM and CpG ODN 1826. Thus DKO B cells only respond to RNA-associated ligands because DNase II-mediated degradation of self-DNA is required for TLR9 activation.

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“…However, it is important to add a distinction here. Autoantibodies to nuclear antigens persist in DNASE2 and STING double knock-out mice, but they are no longer detectable on a background deficient for Unc93b1, the ER-associated chaperone for TLR7 and TLR9 trafficking to endosomes (269, 270). Of note, these autoantibodies were not specific to dsDNA but to RNA-associated antigens perhaps reflecting the excessive accumulation of apoptotic cell debris containing RNA-associated autoantigens (270).…”

Section: Degradation Of Apoptotic Cell Dnamentioning

confidence: 99%

The many ways tissue phagocytes respond to dying cells

Blander

2017

Immunological Reviews

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Summary Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.

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Cutting Edge: AIM2 and Endosomal TLRs Differentially Regulate Arthritis and Autoantibody Production in DNase II–Deficient Mice

Cited by 88 publications

References 18 publications

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

Cutting Edge: DNase II Deficiency Prevents Activation of Autoreactive B Cells by Double-Stranded DNA Endogenous Ligands

The many ways tissue phagocytes respond to dying cells

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