Preprint An interorgan neuroimmune circuit promotes visceral hypersensitivity, 2025, Kim+

[Nightsong]

Abstract:
Visceral pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS) often manifest concurrently in the bladder and colon. Yet, the mechanistic basis of such comorbidities and the transmission of neural hypersensitivity across organ systems has remained a mystery. Here, we identify a mast cell-sensory neuron circuit that initiates bladder inflammation and simultaneously propagates neural hypersensitivity to the colon in a murine model of IC/BPS. We unveil anatomic heterogeneity of mast cells in relation to nociceptors in the bladder and their critical dependence on Mas-related G protein-coupled receptor B2 (MrgprB2) to promote visceral hypersensitivity.

Employing retrograde neuronal tracing, in vivo calcium imaging, and intersectional genetics, we uncover a population of polyorganic sensory neurons that simultaneously innervate multiple organs and exhibit functional convergence. Importantly, using humanized mice, we demonstrate that pharmacological blockade of mast cell-expressed MRGPRX2, the human ortholog of MrgprB2, attenuates both bladder pathology and colonic hypersensitivity. Our studies reveal evolutionarily conserved neuroimmune mechanisms by which immune cells can directly convey signals from one organ to another through sensory neurons, in the absence of physical proximity, representing a new therapeutic paradigm.

Link (ResearchSquare preprint, March 2025, open access)

 

[SNT Gatchaman]

I. Core Findings: The Interorgan Neural Circuit & Mast Cell Role

• Polyorganic Sensory Neurons: The research identifies a specific population of sensory neurons in the dorsal root ganglia (DRG) that respond to signals from multiple organs (bladder and colon in this study). These neurons aren't limited to sensing input from a single organ, suggesting a broader role in coordinating visceral function.
• Mast Cell Activation as a Key Initiator: Mast cells, strategically located in barrier tissues, play a crucial role in initiating this interorgan communication. They respond to inflammation and activate these polyorganic sensory neurons.
• MRGPRX2 as a Critical Mediator: The receptor MRGPRX2 on mast cells is identified as a key player. Activation of MRGPRX2 triggers the release of signals that activate the sensory neurons.
• Interorgan Reflex Arc: The study demonstrates a functional reflex arc between the bladder and colon. Inflammation in the bladder activates mast cells, which then activate sensory neurons that project to both the bladder and the colon, leading to hypersensitivity and dysfunction in both organs.
• Evolutionary Conservation: The mechanisms identified are conserved across species (implied by the study's design and discussion).
• MRGPRX2 Antagonist Effectiveness: Blocking MRGPRX2 with a novel antagonist (EP-001) effectively reduced bladder and colon hypersensitivity and dysfunction in a mouse model.

II. Significance & Implications

• New Understanding of Visceral Pain: This research provides a novel explanation for the complex and often poorly localized nature of visceral pain. The existence of polyorganic sensory neurons suggests that pain signals can be integrated across multiple organs, making it difficult to pinpoint the source.
• Mechanism for Multiorgan Pain Syndromes: The findings offer a potential explanation for syndromes where pain and dysfunction affect multiple organs (e.g., irritable bowel syndrome, chronic pelvic pain).
• Novel Therapeutic Target: MRGPRX2 emerges as a promising therapeutic target for visceral pain and dysfunction. The success of the MRGPRX2 antagonist in the mouse model suggests that similar drugs could be effective in humans.
• Rethinking Visceral Reflexes: The study challenges the traditional view of visceral reflexes as simple, localized responses. It suggests that these reflexes can be more complex and involve coordination between multiple organs.
• Neuroimmune Axis: The research highlights the importance of the neuroimmune axis in regulating visceral function. Immune cells (mast cells) are not just involved in inflammation but also play a critical role in modulating sensory neuron activity.

III. Key Points from the Discussion Section

• Beyond Vagal Sensory Neurons: The study expands our understanding of visceral sensation beyond the traditionally emphasized vagal sensory neurons, highlighting the role of spinal sensory neurons.
• IgE vs. MRGPRX2: The authors differentiate between the role of IgE (involved in allergic responses) and MRGPRX2. While IgE is important for initiating defensive reflexes, MRGPRX2 appears to be more specifically involved in driving nociception and dysfunction in deeper pelvic organs.
• Hijacked Homeostatic Circuits: The authors propose that inflammatory conditions can "hijack" normally functioning homeostatic sensorimotor circuits, leading to enhanced neural hypersensitivity and dysfunction.
• Potential for Broad Applicability: The findings may be relevant to other organ systems beyond the bladder and colon, suggesting that similar interorgan neural circuits may exist throughout the body.

IV. Future Directions

• Human Studies: The most important next step is to investigate the role of MRGPRX2 and polyorganic sensory neurons in human patients with chronic pelvic pain and other visceral pain syndromes.
• Clinical Trials: If the human studies are promising, clinical trials of MRGPRX2 antagonists could be conducted to evaluate their efficacy and safety.
• Identification of Other Interorgan Circuits: Further research is needed to identify other interorgan neural circuits and the mechanisms that regulate them.
• Investigating the Role of Other Immune Cells: The study focused on mast cells, but other immune cells may also play a role in regulating visceral sensation.
• Understanding the Molecular Mechanisms: Further research is needed to understand the molecular mechanisms that regulate the activity of polyorganic sensory neurons.

In essence, this research provides a compelling new framework for understanding visceral pain and dysfunction. It identifies a novel neural circuit and a promising therapeutic target that could lead to more effective treatments for these debilitating conditions.

 

[Murph]

You have to love when vague, general pain symptoms end up having an identifiable neural basis. Another one taken from our old friends the psychologists by good science.

 

[Utsikt]

You have to love when vague, general pain symptoms end up having an identifiable neural basis. Another one taken from our old friends the psychologists by good science.

They’ll just spin it as another win for the gut-brain-axis and neuroplasticity.

 

[Trish]

This was done in mice. I wonder how they detect where in its little body the mouse is experiencing pain.

 

[Utsikt]

This was done in mice. I wonder how they detect where in its little body the mouse is experiencing pain.

I believe they did some live measurements of nerves and lots of probing and insertion of instruments.

There are some diagrams in the figures.

 

[Creekside]

This was done in mice.

"Humanized" mice. I'm picturing mice wearing clothes and using social media.

I do wonder how well modified mice actually represent human biology. Swapping taillights from a sports car isn't going to make an old VW beetle go faster. The article points out just how complex the human body is, so swapping a few genes (if that's what "humanizing" does) isn't going to replicate all the other systems interacting with whatever those genes do.

 

[SNT Gatchaman]

See also Characterisation of MRGPRX2+ mast cells in irritable bowel syndrome (2025, Gut)