IL-3 plays immunoregulatory role in allergic asthma

ByRichard Gawel

The pro-inflammatory protein IL-3 appeared to regulate the burden of allergic asthma by inducing T regulatory cell response and reducing the proliferation of type 2 innate lymphoid cells, according to a study in Frontiers in Immunology.

“We previously investigated the role of IL-3 in mast cell development. However, we noticed that in patients with asthma, the role of IL-3 needed further investigations,” Susetta Finotto, PhD, head of the department of molecular pneumology at Friedrich-Alexander-University Erlangen-Nürnberg in Germany, and Susanne Krammer, RPh, and Zuqin Yang, MSc, PhD students at the university, said in a statement to Healio.

“Furthermore, there were studies demonstrating that IL-3 was produced by T cells involved in the resolution of asthma. We thus decided to further investigate the regulatory role of IL-3 in asthma,” the researchers said.

The researchers examined 24 children with asthma and 21 control children without asthma (age range, 4 to 6 years). During the baseline visit, the researchers collected nasopharyngeal fluid (NPF) and peripheral blood mononuclear cells (PBMCs) from the children.

The control children and the children with controlled asthma had comparable levels of IL-3 in their NPF, the researchers said, but the children with partially uncontrolled asthma had significantly reduced levels. Also, three of the children with uncontrolled asthma had scattered levels.

One child with no NPF IL-3 had worse lung function and higher C-reactive protein, which the researchers called confirmation of a possible role for IL-3 in the amelioration of asthma.

Zuqin Yang

The researchers additionally found increased secretion of IL-3 in PBMCs stimulated with phytohemagglutinin from children with asthma treated with steroids compared with the healthy controls. IL-3 was induced among children with controlled and partially controlled asthma who were treated with steroids as well.

Noting that the soluble form of the ST2 protein (sST2) in the IL-1 family has anti-inflammatory properties, the researchers said they also found a direct correlation between IL-3 and sST2 in the NPF of children with asthma.

This correlation persisted among the children with asthma who were treated with steroids, but it was not seen in the control children. The researchers called this evidence that IL-3 may be involved in the shedding of ST2, neutralizing IL-33 function in the airways.

The researchers also found a significant induction of the IL-3 receptor (IL-3R) alpha chain/ hypoxanthine-guanine phosphoribosyltransferase mRNA expression among the children with controlled asthma and the children who were treated with nonsteroid medications. In controlled asthma, then, IL-3 and its specific receptor alpha chain were upregulated.

Next, the researchers sensitized mice to allergens and treated them with recombinant IL-3 (rIL-3). The mice did not show a significant change in airway hyperresponsiveness or any change in serum IgE levels, but they did experience a trend toward reduced lung inflammation and mucus production and the number of type 2 innate lymphoid cells (ILC2) expressing GATA-binding protein 3 (GATA3) in the lung.

Plus, there was a trend toward upregulation of TGF-beta, which induces Foxp3+ T regulatory cells, in the lungs of mice that were treated with rIL-3 in vivo. When rIL-3 was administered during the challenge phase, CD4+CD25+Foxp3+ T regulatory cells were induced in the lungs of treated mice as well.

Finding an association between IL-3 and steroid-resolved asthma, the researchers said, rIL-3 treatment resulted in the amelioration of airway eosinophilia and mucus production, indicating the potential for new immunotherapy strategies for allergic asthma.

Susanne Krammer

“These results would suggest initiating further investigations on the regulatory and potential protective role of IL-3 in asthma. Further investigations in humans are needed to confirm our novel findings,” the researchers said.

Next, the researchers will study larger cohorts of patients.

“We already have started to recruit patients for a new study in primary school age children, the AGENDAs study, as well as in adults with and without asthma, the AZCRA study, in collaboration with the children’s hospital and the I Medical Clinic in Erlangen, respectively,” the researchers said. “New investigations in IL-3 and IL-3 receptor-deficient mice on the immunological role of IL-3 in asthma are ongoing in our laboratories.”