Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses

Gulsum E. Muku, Tejas S. Lahoti, Iain A. Murray, Michael A. Podolsky, Kayla J. Smith, Troy D. Hubbard, Guray Kuzu, Krishne Gowda, Shantu G. Amin, Gary H. Perdew

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The Ah receptor (AHR) has been shown to exhibit both inflammatory and anti-inflammatory activity in a context-specific manner. In vivo macrophage-driven acute inflammation models were utilized here to test whether the selective Ah receptor modulator 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce inflammation. Exposure to SGA360 was capable of significantly inhibiting lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms of lethality and attenuating inflammatory signaling in tissues. Topical exposure to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU) crystal gout mouse model. Inhibition was dependent on the expression of the high-affinity allelic AHR variant in both acute inflammation models. Upon peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360 attenuated the expression of numerous inflammatory genes and genes known to be directly regulated by AHR in thioglycolate-elicited primary peritoneal macrophages treated with LPS. In addition, expression of the high-affinity allelic AHR variant in cultured macrophages was necessary for SGA360-mediated repression of inflammatory gene expression. Mechanistic studies revealed that SGA360 failed to induce nuclear translocation of the AHR and actually enhanced cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR ligand activity was detected in peritoneal exudates isolated from MSU-treated mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated at least in part through AHR antagonism of endogenous agonist activity. These results underscore an important role of the AHR in participating in acute inflammatory signaling and warrants further investigations into possible clinical applications.

Original languageEnglish (US)
Pages (from-to)1471-1487
Number of pages17
JournalLaboratory Investigation
Volume97
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Macrophages
Ligands
Uric Acid
Lipopolysaccharides
Inflammation
Anti-Inflammatory Agents
Thioglycolates
SGA 360
Gout
Peritoneum
Peritoneal Macrophages
Exudates and Transudates
Septic Shock
Genes
Edema
Neutrophils
Joints
RNA
Gene Expression

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Muku, Gulsum E. ; Lahoti, Tejas S. ; Murray, Iain A. ; Podolsky, Michael A. ; Smith, Kayla J. ; Hubbard, Troy D. ; Kuzu, Guray ; Gowda, Krishne ; Amin, Shantu G. ; Perdew, Gary H. / Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses. In: Laboratory Investigation. 2017 ; Vol. 97, No. 12. pp. 1471-1487.
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abstract = "The Ah receptor (AHR) has been shown to exhibit both inflammatory and anti-inflammatory activity in a context-specific manner. In vivo macrophage-driven acute inflammation models were utilized here to test whether the selective Ah receptor modulator 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce inflammation. Exposure to SGA360 was capable of significantly inhibiting lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms of lethality and attenuating inflammatory signaling in tissues. Topical exposure to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU) crystal gout mouse model. Inhibition was dependent on the expression of the high-affinity allelic AHR variant in both acute inflammation models. Upon peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360 attenuated the expression of numerous inflammatory genes and genes known to be directly regulated by AHR in thioglycolate-elicited primary peritoneal macrophages treated with LPS. In addition, expression of the high-affinity allelic AHR variant in cultured macrophages was necessary for SGA360-mediated repression of inflammatory gene expression. Mechanistic studies revealed that SGA360 failed to induce nuclear translocation of the AHR and actually enhanced cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR ligand activity was detected in peritoneal exudates isolated from MSU-treated mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated at least in part through AHR antagonism of endogenous agonist activity. These results underscore an important role of the AHR in participating in acute inflammatory signaling and warrants further investigations into possible clinical applications.",
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Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage-mediated acute inflammatory responses. / Muku, Gulsum E.; Lahoti, Tejas S.; Murray, Iain A.; Podolsky, Michael A.; Smith, Kayla J.; Hubbard, Troy D.; Kuzu, Guray; Gowda, Krishne; Amin, Shantu G.; Perdew, Gary H.

In: Laboratory Investigation, Vol. 97, No. 12, 01.12.2017, p. 1471-1487.

Research output: Contribution to journalArticle

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AU - Muku, Gulsum E.

AU - Lahoti, Tejas S.

AU - Murray, Iain A.

AU - Podolsky, Michael A.

AU - Smith, Kayla J.

AU - Hubbard, Troy D.

AU - Kuzu, Guray

AU - Gowda, Krishne

AU - Amin, Shantu G.

AU - Perdew, Gary H.

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