Induction of autoimmunity by pristane and other naturally occurring hydrocarbons

Reeves, Westley H.; Lee, Pui Y.; Weinstein, Jason S.; Satoh, Minoru; Lü, Li

doi:10.1016/j.it.2009.06.003

Cited by 343 publications

(424 citation statements)

References 90 publications

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“…STING-deficient MRL/lpr mice develop a dramatically accelerated disease profile characterized by the expansion and activation of both the lymphoid and myeloid compartments, increased numbers of type I IFN-producing cells, elevated autoantibody titers, and a shorter lifespan. Similar to our findings in the MRL/lpr model, STING deficiency exacerbated TMPD-induced inflammation, a condition also associated with type I IFNs and TLR-activated Ly6C hi monocytes (24,26). Nonautoimmune-prone STING-deficient mice do not exhibit any evidence of systemic autoimmunity.…”

Section: Discussionsupporting

confidence: 88%

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Suppression of systemic autoimmunity by the innate immune adaptor STING

Sharma

Campbell

Chan

et al. 2015

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

148

139

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Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.

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Section: Discussionsupporting

confidence: 88%

“…injection of the hydrocarbon oil TMPD (also known as "pristane"). These features include a type I IFN signature, ANAs, and glomerulonephritis (24,25). Importantly, TMPD-induced autoimmunity is dependent upon TLR7 and type I IFNs (26).…”

Section: Sting Deficiency Results In the Increased Expression Of Ifn-mentioning

confidence: 99%

Suppression of systemic autoimmunity by the innate immune adaptor STING

Sharma

Campbell

Chan

et al. 2015

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

148

139

View full text Add to dashboard Cite

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“…In the pristane model of experimental murine lupus, injection of pristane oil triggers a chronic inflammatory response that is paralleled by an increased rate of apoptotic and necrotic cell death (39). Although WT mice are able to cope with this situation, alterations in the noninflammatory clearance of ACs, such as the deletion of Tim4 (40) or absence of Nr4a1, eventually result in the break of self-tolerance to AC-derived Ags.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Ipseiz

Uderhardt

Scholtysek

et al. 2014

The Journal of Immunology

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Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-κB signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-κB signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to “dying self.”

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“…Previous attempts to immunize nonautoimmune mice with self-antigens, such as DNA, apoptotic cells, or purified nucleosome, only resulted in limited or transient autoantibody generation (36)(37)(38). Tetramethylpentadecane (TMPD) induces an array of autoantibodies and glomerulonephritis in BALB/c mice (39). Interestingly, prolonged oral administration of TMPD reportedly leads to amyloidosis (40).…”

Section: Discussionmentioning

confidence: 99%

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

Domizio¹,

Dorta‐Estremera²,

Gagea

et al. 2012

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

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The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of selfantigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.autoimmune disease | innate immune response | disease model

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Induction of autoimmunity by pristane and other naturally occurring hydrocarbons

Cited by 343 publications

References 90 publications

Suppression of systemic autoimmunity by the innate immune adaptor STING

Suppression of systemic autoimmunity by the innate immune adaptor STING

The Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

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