Aryl Hydrocarbon Receptor Activation Ameliorates Acute Respiratory Distress Syndrome through Regulation of Th17 and Th22 Cells in the Lungs

Holloman, Bryan Latrell; Cannon, Alkeiver S; Wilson, Kiesha; Nagarkatti, Prakash; Nagarkatti, Mitzi

doi:10.1128/mbio.03137-22

Cited by 9 publications

(4 citation statements)

References 80 publications

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“…The aryl hydrocarbon receptor (AhR) is a transcription factor expressed in skin cells such as keratinocytes, mast cells, and melanocytes. [531][532][533] AhR signaling has been shown to regulate Th17 and Th22 cell differentiation, as well as the expression of IL-17 and IL-22, 534,535 which have been found to increase in the psoriatic skin in AhR-deficient mice. 536 Tapinarof is a topical aryl hydrocarbon receptor modulator separated from a variety of symbiotic bacterial metabolites.…”

Section: Other Clinical Research Progressmentioning

confidence: 99%

Signaling pathways and targeted therapies for psoriasis

Guo,

Zhang,

Lin

et al. 2023

Sig Transduct Target Ther

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Psoriasis is a common, chronic, and inflammatory skin disease with a high burden on individuals, health systems, and society worldwide. With the immunological pathologies and pathogenesis of psoriasis becoming gradually revealed, the therapeutic approaches for this disease have gained revolutionary progress. Nevertheless, the mechanisms of less common forms of psoriasis remain elusive. Furthermore, severe adverse effects and the recurrence of disease upon treatment cessation should be noted and addressed during the treatment, which, however, has been rarely explored with the integration of preliminary findings. Therefore, it is crucial to have a comprehensive understanding of the mechanisms behind psoriasis pathogenesis, which might offer new insights for research and lead to more substantive progress in therapeutic approaches and expand clinical options for psoriasis treatment. In this review, we looked to briefly introduce the epidemiology, clinical subtypes, pathophysiology, and comorbidities of psoriasis and systematically discuss the signaling pathways involving extracellular cytokines and intracellular transmission, as well as the cross-talk between them. In the discussion, we also paid more attention to the potential metabolic and epigenetic mechanisms of psoriasis and the molecular mechanistic cascades related to its comorbidities. This review also outlined current treatment for psoriasis, especially targeted therapies and novel therapeutic strategies, as well as the potential mechanism of disease recurrence.

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Section: Other Clinical Research Progressmentioning

confidence: 99%

Signaling pathways and targeted therapies for psoriasis

Guo,

Zhang,

Lin

et al. 2023

Sig Transduct Target Ther

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“…LPS-mediated ARDS in mice was induced as described ( 52 , 53 ). Briefly, mice were anesthetized with isoflurane in combination with oxygen.…”

Section: Methodsmentioning

confidence: 99%

“…After 48 hours, mice were euthanized for studies on ARDS. The dose, frequency, and route of I3C was standardized based on our previous studies ( 52 , 53 ).…”

Section: Methodsmentioning

confidence: 99%

Indole-3-carbinol attenuates lipopolysaccharide-induced acute respiratory distress syndrome through activation of AhR: role of CCR2+ monocyte activation and recruitment in the regulation of CXCR2+ neutrophils in the lungs

Holloman,

Wilson,

Cannon

et al. 2024

Front. Immunol.

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IntroductionIndole-3-carbinol (I3C) is found in cruciferous vegetables and used as a dietary supplement. It is known to act as a ligand for aryl hydrocarbon receptor (AhR). In the current study, we investigated the role of AhR and the ability of I3C to attenuate LPS-induced Acute Respiratory Distress Syndrome (ARDS).MethodsTo that end, we induced ARDS in wild-type C57BL/6 mice, Ccr2gfp/gfp KI/KO mice (mice deficient in the CCR2 receptor), and LyZcreAhRfl/fl mice (mice deficient in the AhR on myeloid linage cells). Additionally, mice were treated with I3C (65 mg/kg) or vehicle to investigate its efficacy to treat ARDS.ResultsI3C decreased the neutrophils expressing CXCR2, a receptor associated with neutrophil recruitment in the lungs. In addition, LPS-exposed mice treated with I3C revealed downregulation of CCR2+ monocytes in the lungs and lowered CCL2 (MCP-1) protein levels in serum and bronchoalveolar lavage fluid. Loss of CCR2 on monocytes blocked the recruitment of CXCR2+ neutrophils and decreased the total number of immune cells in the lungs during ARDS. In addition, loss of the AhR on myeloid linage cells ablated I3C-mediated attenuation of CXCR2+ neutrophils and CCR2+ monocytes in the lungs from ARDS animals. Interestingly, scRNASeq showed that in macrophage/monocyte cell clusters of LPS-exposed mice, I3C reduced the expression of CXCL2 and CXCL3, which bind to CXCR2 and are involved in neutrophil recruitment to the disease site.DiscussionThese findings suggest that CCR2+ monocytes are involved in the migration and recruitment of CXCR2+ neutrophils during ARDS, and the AhR ligand, I3C, can suppress ARDS through the regulation of immune cell trafficking.

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“…Using the bleomycin mouse model of pulmonary fibrosis, we demonstrate that AHR+ DCs accumulate in the lungs and drive production of IL-6 in an AHR dependent fashion. AHR plays a role in differentiation of several immune cells, including Treg, Th-17 and Th-22 cells (31)(32)(33), which makes whole-body knock outs non-ideal for studying immune responses. Using a DC-specific deletion of the DNA binding region of AHR (CD11c-Cre / AHR Δex2), we further demonstrate deletion of canonical AHR function in DCs leads to significant upregulation of ncAHR signaling, pro-inflammatory cytokines and worsened fibrosis in the bleomycin model.…”

Section: Introductionmentioning

confidence: 99%

Dendritic Cell – Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis

Carter,

Costa,

Adams

et al. 2024

Preprint

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Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2-5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and IL-17, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with bleomycin developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2. Study of human samples corroborate the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

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Aryl Hydrocarbon Receptor Activation Ameliorates Acute Respiratory Distress Syndrome through Regulation of Th17 and Th22 Cells in the Lungs

Abstract: Acute respiratory distress syndrome (ARDS) is a type of respiratory failure that is triggered by a variety of bacterial and viral infections, including the coronavirus SARS-CoV2. ARDS is associated with a hyperimmune response in the lungs that which is challenging to treat.

Cited by 9 publications

References 80 publications

Signaling pathways and targeted therapies for psoriasis

Signaling pathways and targeted therapies for psoriasis

Indole-3-carbinol attenuates lipopolysaccharide-induced acute respiratory distress syndrome through activation of AhR: role of CCR2+ monocyte activation and recruitment in the regulation of CXCR2+ neutrophils in the lungs

Dendritic Cell – Fibroblast Crosstalk via TLR9 and AHR Signaling Drives Lung Fibrogenesis

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