Geoffrey Chupp, MD, Yale School of Medicine 

Alarmins and TSLP and Upstream Drivers of Severe Asthma Inflammation

This episode, "Alarmins and TSLP: Upstream Drivers of Severe Asthma Inflammation," features Dr. Hanania tracing 32 years of shifting thinking about what starts airway inflammation.

Dr. Chupp asks Dr. Hanania how he thinks about the role of alarmins in driving the inflammatory response. Dr. Hanania begins with his own training. When he started, thinking about asthma and upper airway inflammation was, in his word, naive. Clinicians knew inflammation existed but not what drove it. The field responded by looking downstream. Eosinophilic inflammation was identified and then treated, and inhaled steroids became a good answer to it. What was missing was the question of what starts the process in the first place.

That question, he says, is where the epithelial barrier becomes central. The barrier is not simply present; it gets injured. He lists the insults that injure it: allergens, the adaptive immune response, pollutants, environmental exposures, and microbes. The specific trigger matters less than the result. Injury means loss of barrier function, and lost barrier function sends a downstream signal through the alarmins.

Dr. Hanania then makes the case for TSLP specifically, building on Dr. Wechsler's earlier point. He calls TSLP a master regulator cytokine because it drives downstream signaling of type 2 inflammation through both adaptive and innate immune responses. Critically, it also drives the non-type 2 pathway. He flags that pathway as an unmet need, because clinicians have very few good targets there. This is what pushed the field to think outside the box, he says: if these epithelial cytokines can be blocked, the downstream signal may be prevented before it starts. The result would be reduced airway inflammation through several different routes and mechanisms at once, rather than the single downstream pathway that most current therapies address.

Our next episode, "Asthma Phenotypes and Endotypes: Defining the Terms," turns to the vocabulary clinicians use to sort asthma types.

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One cytokine sits above the rest. Dr. Hanania explains why TSLP earns the label of master regulator, and why blocking it reaches inflammation that current therapies cannot.

Rethinking Severe Asthma: The Airway Epithelium as an Immune Organ

Welcome back to another HCPLive Peer Exchange series. In "Rethinking Severe Asthma: The Airway Epithelium as an Immune Organ," moderator Geoffrey Chupp, MD is joined by Jacqueline Ross, MD, Michael E. Wechsler, MD, MMSc, and Nicola A. Hanania, MD, MS to open the series on severe asthma and upper airway disease.

Dr. Chupp frames the opening question for Dr. Ross, whose allergy career centered on the immunologic side of airway disease. Dr. Ross says clinicians once pictured the epithelium as a brick wall built only to keep things out. That picture no longer holds. She describes the epithelium as an immune system and an organ in its own right. It produces chemicals and cytokines that recruit cells to the site to fight pathogens. It holds mediators such as IgA at the surface that neutralize threats on contact. Innate immune cells sit there ready to activate against viral, bacterial, and other pathogens. The tissue can also drive an adaptive response and build a kind of protective memory. When that system is disrupted, she explains, inflammation and irritation follow, producing airway remodeling, excess mucus, and further destruction of the epithelium itself.

Dr. Wechsler agrees and extends the point to mechanism. He describes an immune-modulating tissue that releases cytokines capable of shaping the entire immune response. The epithelial cytokines, or alarmins, include IL-25, IL-33, and thymic stromal lymphopoietin. These activate TH2 cells and innate lymphoid cells, which in turn release the cytokines that drive asthma. He walks through each one. IL-4 fuels the allergic pathway and downstream IgE production. IL-5 drives the activation, proliferation, and maturation of eosinophils. IL-13 plays what he calls a variegated set of roles, contributing to mucus production, airway hyperresponsiveness, fibrosis, and nitric oxide. His conclusion sets up the series: acting at the epithelial layer produces consequences across many cells and many cytokines at once.

The next episode in this series, "Alarmins and TSLP and Upstream Drivers of Severe Asthma Inflammation," features Dr. Hanania on why one epithelial cytokine sits above all the others.

The airway epithelium is no longer understood as a passive wall. The panel traces how a barrier is now thought of as an immune organ, and what that shift means for severe asthma.

Geoffrey Chupp, MD, Yale School of Medicine

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