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Open Access | 
10.1172/JCI199952
Braking the system: the aryl hydrocarbon receptor controls monocytes in homeostasis
Jessica E. Kenison1,2,3 and Francisco J. Quintana1,2,3
1Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Ann Romney, Center for Neurologic Diseases, 60 Fenwood Rd., Boston, Massachusetts 02115, USA. Phone: 617.525.5317; Email: fquintana@rics.bwh.harvard.edu.
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1Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
3Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Ann Romney, Center for Neurologic Diseases, 60 Fenwood Rd., Boston, Massachusetts 02115, USA. Phone: 617.525.5317; Email: fquintana@rics.bwh.harvard.edu.
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Published December 1, 2025 - More info
J Clin Invest. 2025;135(23):e199952. https://doi.org/10.1172/JCI199952.
© 2025 Kenison,, et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Immune cells are constantly exposed to microbiota-derived compounds that can engage innate recognition receptors. How this constitutive stimulation is downmodulated to avoid systemic inflammation and autoimmunity is poorly understood. Here, we show that aryl hydrocarbon receptor (AhR) deficiency in monocytes unleashed spontaneous cytokine responses in vivo, driven by stimulator of interferon genes (STING)-mediated tonic sensing of microbiota. This effect was specific to monocytes, as mice deficient for AhR specifically in macrophages did not show any dysregulation of tonic cytokine responses. AhR inhibition also increased tonic cytokine production in human monocytes. Finally, in patients with systemic juvenile idiopathic arthritis, low AhR activity in monocytes correlated with elevated cytokine responses. Our findings reveal an essential role for AhR in monocytes in restraining tonic microbiota sensing and in maintaining immune homeostasis.
Authors
Adeline Cros, Alessandra Rigamonti, Alba de Juan, Alice Coillard, Mathilde Rieux-Laucat, Darawan Tabtim-On, Emeline Papillon, Christel Goudot, Alma-Martina Cepika, Romain Banchereau, Virginia Pascual, Marianne Burbage, Burkhard Becher, Elodie Segura
The immune system is continuously exposed to diverse microbial and dietary stimulants, many of which interact with innate immune recognition receptors (1, 2). This low-level, or “tonic,” stimulation is important for immune maturation, regulation, and tissue homeostasis but, if left uncontrolled, can contribute to chronic inflammation or autoimmunity (3, 4). Recent studies have investigated mechanisms that regulate baseline inflammatory signaling and prevent inappropriate immune activation, but regulatory pathways participating in the cell type–specific control of tonic microbial sensing remain incompletely characterized. In a recent study, Cros et al. demonstrated a role for the aryl hydrocarbon receptor (AhR) in limiting monocyte proinflammatory responses to microbiota-derived cues, providing insight into the molecular networks that maintain immune balance (5).
The AhR was first identified as a sensor for environmental pollutants such as dioxins and polychlorinated biphenyls (6, 7). However, accumulating evidence demonstrates that the AhR acts as a physiological regulator of the immune system, integrating signals from endogenous, microbial, and dietary ligands (4, 8, 9). These AhR agonists induce a broad range of immunologic effects depending on ligand type, cell type, and tissue microenvironment, with consequences for both innate and adaptive immunity (4, 10, 11).
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The AhR limits monocyte inflammatory responses to microbiota
In this issue of the Journal, Cros et al. used conditional genetic deletion to assess the AhR’s function in murine monocytes (5). They report that AhR deficiency in monocytes, but not in macrophages, resulted in increased spontaneous systemic inflammation, as evidenced by the upregulation of type I IFN-stimulated genes and increases in plasma TNF and chemokine levels (Figure 1) (5). Further analyses established that these proinflammatory effects of AhR inactivation in monocytes were dependent on microbiota-derived signals and the stimulator of IFN gene (STING) pathway, which is involved in cytosolic DNA sensing (12). Indeed, treating AhR-deficient mice with broad-spectrum antibiotics reversed this proinflammatory response, as did genetic deletion of STING, highlighting the importance of tonic microbiota sensing as a driver of immune dysregulation in the absence of AhR signaling (5).
Figure 1The AhR functions as a homeostatic brake on monocyte responses to microbiota. (A) The AhR restrains proinflammatory cytokine output by suppressing STING signaling, a function that maintains systemic immune balance. (B) Cros et al. reported that AhR deficiency in monocytes produced a proinflammatory response to tonic sensing of microbiota-derived signals (5).
Complementary ex vivo experiments in primary human monocytes revealed that AhR pharmacologic inhibition led to elevated cytokine production, recapitulating the findings in mice. In addition, the analysis of monocytes in systemic juvenile idiopathic arthritis (sJIA), a condition characterized by systemic inflammation, revealed both suppressed AhR activity and increased proinflammatory gene signatures, supporting the relevance of the AhR for the regulation of monocytes in human diseases (5).
This study adds to a growing body of work on the function of the AhR in immune homeostasis. The AhR has been implicated in modulating both innate and adaptive responses, for example by suppressing NF-κB and STING signaling, promoting Treg function, and maintaining barrier integrity (4, 11, 13, 14). Cros et al. suggest that monocyte-specific AhR activity serves to limit proinflammatory cytokine responses to persistent microbial stimulation. Notably, this role is not mirrored in macrophages, suggesting differences in developmental origin, chromatin landscape, or environmental exposure as potential determinants of AhR function (5). Further mechanistic studies are required to define the basis for these cell type–specific effects.
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