Mouse model uncovers how lung cells manage severe asthma inflammation

A better understanding of inflammation and lung immunity over the past two decades has led to new, innovative treatments for asthma, including biologic therapies. This is especially true for a subtype known as eosinophilic asthma—asthma that’s related to the recruitment and overactivation of white blood cells in the lungs called eosinophils.

However, a different type of asthma called neutrophilic asthma has fewer treatment options and doesn’t respond as well to first-line asthma therapy. As a result, people with this type of asthma, which is usually diagnosed in adults, often experience more serious disease and a poorer quality of life.

A team of researchers led by Anukul Shenoy, Ph.D., of the Department of Microbiology and Immunology and the Division of Pulmonary and Critical Care Medicine at U-M and Joseph Mizgerd, Ph.D., of Boston University Chobanian & Avedisian School of Medicine, is trying to address a lack of knowledge around neutrophilic asthma and have developed one of the first mouse models for the condition.

The paper is published in the journal Cell Reports.

By repeatedly but briefly exposing mice to an inhaled allergen over time, the researchers were able to mimic the exposure and immune activity within the airways of adult humans.

This type of allergen exposure resulted in an increase in accumulation of different types of T cells called CD4+TRM cells—memory cells that are present in adult lungs and responsible for a rapid response to a previously encountered allergen.

When activated, one subset of CD4+TRM cells lining the airways produces a cytokine called IL-17A, which then persuades the epithelial cells of the lung to recruit neutrophils, a type of white blood cell that causes inflammation.

While neutrophils are important for protection against pathogens, their activation in response to a harmless allergen in asthmatics leads to severe lung damage.

Interestingly, the team also discovered that the epithelial cells try and control this inflammation by using a specialized immune-facing molecule called MHC-II.

They do so by using MHC-II to instruct a different subset of CD4+TRM cells in the airways to produce a cytokine IFN-gamma, which then potently suppressed inflammation in this mouse model of neutrophilic asthma.