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.