Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

Yoon, Gi Sang; Sud, Sudha; Keswani, Rahul K.; Baik, Jason; Standiford, Theodore J.; Stringer, Kathleen A.; Rosania, Gus R.

doi:10.1021/acs.molpharmaceut.5b00035

Cited by 45 publications

(57 citation statements)

References 65 publications

(149 reference statements)

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“…CLDIs were isolated from the spleen of 8 week CFZ fed mice using a previously described method [21]. In brief, the spleens were homogenized with a syringe plunger and then filtered through a 40 μm cell strainer to remove connective tissue debris.…”

Section: Isolation Of Spleen Cldismentioning

confidence: 99%

“…Based off of previous work, it has been shown that CLDIs tend to be found within tissue macrophages, such as Kupffer cells of the liver, red pulp macrophages of the spleen, and alveolar macrophages within the lung [18,28,29]. Due to the extensive accumulation within alveolar macrophages, these cells were chosen to test this multi-parameter imaging and analysis system in live cells.…”

Section: Multi-parameter Live Cell Imaging and Quantification Of Diatmentioning

confidence: 99%

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Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Rzeczycki

Yoon

Keswani

et al. 2017

Biomed. Opt. Express

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Abstract:Following prolonged administration, certain orally bioavailable but poorly soluble small molecule drugs are prone to precipitate out and form crystal-like drug inclusions (CLDIs) within the cells of living organisms. In this research, we present a quantitative multiparameter imaging platform for measuring the fluorescence and polarization diattenuation signals of cells harboring intracellular CLDIs. To validate the imaging system, the FDAapproved drug clofazimine (CFZ) was used as a model compound. Our results demonstrated that a quantitative multi-parameter microscopy image analysis platform can be used to study drug sequestering macrophages, and to detect the formation of ordered molecular aggregates formed by poorly soluble small molecule drugs in animals.

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Section: Isolation Of Spleen Cldismentioning

confidence: 99%

Section: Multi-parameter Live Cell Imaging and Quantification Of Diatmentioning

confidence: 99%

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Rzeczycki

Yoon

Keswani

et al. 2017

Biomed. Opt. Express

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“…Furthermore, in vitro studies have shown that intracellular CFZ biocrystals dampen proinflammatory pathways while enhancing anti-inflammatory signals (23).…”

mentioning

confidence: 99%

Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State

Yoon

Keswani

Sud

et al. 2016

Antimicrob Agents Chemother

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Clofazimine (CFZ) is a poorly soluble antibiotic and anti-inflammatory drug indicated for the treatment of leprosy. In spite of its therapeutic value, CFZ therapy is accompanied by the formation of drug biocrystals that accumulate within resident tissue macrophages, without obvious toxicological manifestations. Therefore, to specifically elucidate the off-target consequences of drug bioaccumulation in macrophages, we compared the level of inflammasome activation in CFZ-accumulating organs (spleen, liver and lung) in mice after 2 and 8 weeks of CFZ treatment when the drug exists in soluble and insoluble (biocrystalline) forms, respectively. Surprisingly, the results showed a drastic reduction in caspase 1 and interleukin-1␤ (IL-1␤) cleavage in the livers of mice treated with CFZ for 8 weeks (8-week-CFZ-treated mice) compared to 2-week-CFZ-treated and control mice, which was accompanied by a 3-fold increase in hepatic IL-1 receptor antagonist (IL-1RA) production and a 21-fold increase in serum IL-1RA levels. In the lung and spleen, IL-1␤ cleavage and tumor necrosis factor alpha expression were unaffected by soluble or biocrystal CFZ forms. Functionally, there was a drastic reduction of carrageenan-and lipopolysaccharide-induced inflammation in the footpads and lungs, respectively, of 8-week-CFZ-treated mice. This immunomodulatory activity of CFZ biocrystal accumulation was attributable to the upregulation of IL-1RA, since CFZ accumulation had minimal effect in IL-1RA knockout mice or 2-week-CFZ-treated mice. In conclusion, CFZ accumulation and biocrystal formation in resident tissue macrophages profoundly altered the host's immune system and prompted an IL-1RA-dependent, systemic anti-inflammatory response.

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“…IL1ra-deficient mice exhibit excessive inflammation when bred to various disease models, and patients with IL1RA deficiency show severe inflammatory conditions (14)(15)(16)(17)(18)(19). The icIL1RA isoforms are considered a reservoir of biologic active IL1RA, but the factors that regulate the release of icIL1RA have not been studied in detail (6,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Cells Release IL1 Receptor Antagonist in Response to Genotoxic Stress

Chwee

Khatoo

Tan

et al. 2016

Cancer Immunology Research

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Apoptosis is a controlled means of eliminating damaged cells without causing an inflammatory response or tissue damage. The mechanisms that contribute to the suppression of an inflammatory response upon apoptosis of cells are poorly understood. Here, we report that apoptotic cells release the interleukin-1 receptor antagonist (IL1RA). The release of IL1RA depended on the DNA damage response, caspase 9, and caspase 3. De novo translation, classical secretion pathways, or N-glycosylation was not required for the release of IL1RA. The amounts of IL1RA released by apoptotic cells impaired IL1-induced expression of IL6. In summary, we demonstrate that the release of IL1RA in response to genotoxic stress contributes to the immunosuppressive effects of apoptotic cells.

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Phagocytosed Clofazimine Biocrystals Can Modulate Innate Immune Signaling by Inhibiting TNFα and Boosting IL-1RA Secretion

Cited by 45 publications

References 65 publications

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Detecting ordered small molecule drug aggregates in live macrophages: a multi-parameter microscope image data acquisition and analysis strategy

Clofazimine Biocrystal Accumulation in Macrophages Upregulates Interleukin 1 Receptor Antagonist Production To Induce a Systemic Anti-Inflammatory State

Apoptotic Cells Release IL1 Receptor Antagonist in Response to Genotoxic Stress

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