Scientists have pinpointed a self-perpetuating inflammatory mechanism that explains why nasal polyps often return despite medical and surgical treatment. The findings reveal a persistent “biological memory” within the cells lining the sinuses, driven by a vicious cycle of chemical signals that maintains inflammation long after the initial trigger has vanished. This breakthrough offers a new understanding of chronic rhinosinusitis with nasal polyps (CRSwNP) and illuminates a clear path toward developing more effective, targeted therapies to break the cycle of recurrence that affects millions of people worldwide.
The research, published in Nature, identifies a specific feedback loop between the sinus’s surface epithelial cells and a class of immune cells known as group 2 innate lymphoid cells (ILC2s). Investigators found that epithelial cells, when stressed, release molecular “alarmins” that activate ILC2s. These immune cells, in turn, release signals that not only promote inflammation but also command the epithelial cells to proliferate and produce even more alarmins. This discovery of a self-sustaining loop provides the first cellular explanation for the notoriously high recurrence rate of the condition and suggests that future treatments must disrupt this internal memory to achieve lasting relief.
Anatomy of a Stubborn Condition
Chronic rhinosinusitis with nasal polyps is a severe form of chronic sinus inflammation characterized by the growth of noncancerous, teardrop-shaped polyps on the lining of the nasal passages and sinuses. The condition affects up to 4 percent of the population, causing persistent symptoms including severe nasal congestion, loss of smell and taste, facial pressure, and drainage. Patients often endure a frustrating cycle of treatments, including long-term steroid sprays and oral steroids, which can have significant side effects. For many, surgery to remove the polyps becomes necessary, yet recurrence rates remain high, with polyps returning within a few years for a majority of patients.
The core of the problem lies in what immunologists call type 2 inflammation, the same underlying response seen in other conditions like asthma and eczema. This type of inflammation is driven by a specific set of immune cells and signaling molecules. While triggers like allergens, fungi, or pollutants can initiate the process, clinicians have long been puzzled by why the inflammation continues unabated and why polyps regrow so aggressively. Standard treatments manage symptoms but fail to address the root biological process that drives this persistence, a process that researchers now understand is encoded within the tissue itself.
Uncovering a Vicious Feedback Loop
The investigation homed in on the complex communication network between the structural cells of the sinus lining and the resident immune cells. Using advanced molecular techniques, the team mapped out the interactions that fuel the runaway inflammation characteristic of CRSwNP.
The Role of Epithelial Alarmins
The process begins with the epithelium, the thin layer of cells that serves as the first line of defense in the sinuses. When these cells are damaged or stressed by irritants, they release distress signals called alarmins. The study focused on a specific alarmin, interleukin-33 (IL-33), which acts like a flare sent up from a damaged barrier. In healthy tissue, this response is temporary and helps recruit immune cells to handle a threat. However, in patients with CRSwNP, the researchers found that the epithelial cells were continuously producing high levels of IL-33, keeping the immune system in a permanent state of high alert.
Activating the Immune Responders
This constant stream of IL-33 activates group 2 innate lymphoid cells. ILC2s are powerful players in the immune system, specializing in orchestrating type 2 inflammatory responses. Once activated by IL-33, they ramp up production of their own signaling molecules, primarily the cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13). These cytokines are well-known drivers of inflammation; they recruit other immune cells like eosinophils and promote mucus production, contributing directly to the symptoms of sinusitis and the formation of polyps.
A Self-Sustaining Cycle
The study’s critical insight was discovering what happens next. The IL-13 released by the ILC2s signals back to the epithelial cells, creating a closed, positive feedback loop. This signal instructs the epithelial cells to undergo changes that worsen the disease, including proliferation—which contributes to the bulk of the polyp tissue—and, crucially, to produce even more of the alarmin IL-33. “We have discovered a ‘vicious cycle’ of inflammation in the epithelial cells that line the sinuses,” explained senior author Dr. Benjamin S. Bleier of Mass Eye and Ear. “This study is the first to identify the cellular ‘biological memory’ that accounts for the high recurrence rate of nasal polyps.” This cycle becomes independent of the original trigger, meaning that even after an allergen is removed or an infection is cleared, the tissue remains programmed to sustain its own inflammation.
From Laboratory Models to Human Tissue
To confirm this feedback loop, the research team employed a multi-pronged approach combining studies of human tissue with experiments in animal models. They collected polyp tissue from patients undergoing sinus surgery and compared it to healthy tissue from control subjects. Using a powerful technique called single-cell RNA sequencing, they were able to analyze the genetic activity of thousands of individual cells, identifying the specific cell types involved and the molecular messages being sent between them. This high-resolution analysis allowed them to map the IL-33 and IL-13 signaling pathways connecting epithelial cells and ILC2s.
The team then validated these findings in laboratory models. In experiments using mouse models of sinusitis, they demonstrated that they could induce the inflammatory cycle. More importantly, they showed that blocking a key component of the loop—such as the receptor for IL-33 on the ILC2s—could interrupt the cycle and reduce the inflammation and polyp formation. This crucial step demonstrated a direct cause-and-effect relationship and proved that the feedback loop is not just a correlation but a central driver of the disease.
New Pathways for Targeted Therapies
This detailed understanding of the polyp-perpetuating mechanism opens the door for a new generation of more precise treatments. Current biologic drugs for CRSwNP, such as those that block IL-5 or IL-13, are considered “downstream” therapies because they target the molecules produced after the immune cells have already been activated. While often effective, they do not stop the initial alarm signals.
The new research suggests that “upstream” interventions could be more effective at providing a long-term solution. By targeting the alarmin IL-33 or its receptor, it may be possible to prevent the activation of ILC2s in the first place, thereby shutting down the entire inflammatory cascade before it gains momentum. Blocking this initial step could effectively erase the tissue’s biological memory of inflammation, offering a better chance of preventing polyp recurrence. Several pharmaceutical companies are already developing therapies that target the IL-33 pathway, and this study provides a strong rationale for their application in CRSwNP.
A Common Thread in Chronic Disease
The discovery also has broader implications for a range of chronic inflammatory conditions. The central role of the IL-33/ILC2 axis is a common theme in other type 2 inflammatory diseases, including severe asthma and atopic dermatitis. The finding that epithelial cells can harbor a self-sustaining memory of inflammation may help explain the chronic and relapsing nature of these diseases as well.
This work reinforces a paradigm shift in immunology that places the body’s own barrier tissues, like the skin and the linings of the airways and gut, at the center of chronic disease. Rather than just being passive shields, these epithelial layers are now understood to be active participants that can both initiate and perpetuate inflammatory cycles. Future research will likely explore whether similar feedback loops drive pathology in other organ systems, potentially leading to a unified therapeutic approach for a wide spectrum of persistent inflammatory disorders.