Regulatory pathway revealed for ILC2-mediated pulmonary inflammation
medwireNews: Suppression of type 2 innate lymphoid cells (ILC2) by activated plasmacytoid dendritic cells (pDCs) could present a regulatory pathway for pulmonary inflammation, early research suggests.
“Our findings offer a novel approach for fulfilling the currently unmet clinical requirement for fast-acting immunotherapy for asthma,” say Omid Akbari (University of Southern California, Los Angeles, USA) and colleagues in The Journal of Allergy and Clinical Immunology.
They found that in mice lacking B and T cells, activating pDCs using the intranasal toll-like receptor 7/8 agonist R848 suppressed ILC2- airway hyper-reactivity, as demonstrated by increased lung resistance in response to the allergen Alternaria alternata.
Administering A. alternata increased the number of eosinophils in bronchoalveolar lavage fluid and the total number of ILC2s in the lungs, compared with a phosphate-buffered saline control, but the increase was significantly less in both cases if R848 was administered prior to A. alternata.
Accompanying these changes, there was a notable increase in the thickness of airway epithelium and inflammation around the airways in response to A. alternata that was diminished by R848.
The direct role of pDCs in this immune response was demonstrated using BDCA-2–DTR transgenic mice that have depleted pDCs. In these mice, administration of R848 had no effect on lung resistance and airway hyper-reactivity in response to interleukin (IL)-33.
And suppression of IL-33–induced airway eosinophilia with R848 was abrogated by depletion of pDCs, as evident by a lack of difference in the number of eosinophils between normal mice receiving IL-33 and R848-treated pDC-depleted mice.
In further experiments, the team found that the process by which pDC activation affects ILC2 function appears to involve the suppression of cytokine production by ILC2s, notably of IL-5 and IL-13, and this is mediated by early interferon (IFN)-α production. Blocking IFN-α production with anti- IFN-α antibodies prevented an ILC2s response to R848, ruling out a direct effect of R848.
The mediating effect of IFN-α was also seen in in vivo experiments involving mice lacking the ifnar1 gene. pDCs from the spleens and lungs of wild-type mice, activated ex vivo with R848 and washed, significantly suppressed the number of eosinophils in response to IL-33 administration in wild-type mice but not those lacking ifnar1.
And IFN-α was sufficient to suppress ILC2-mediated airway hyper-reactivity and airway inflammation in mice lacking mature B and T cells, significantly decreasing the number of eosinophils in bronchoalveolar lavage fluid and lung resistance compared with mice treated with IL-33 alone.
RNA sequencing of ILC2s suggested that IFN-α production mediates the suppressing effects of pDC activation by increasing the expression of proapoptotic genes, while decreasing the expression of proliferation and stimulatory genes and this was confirmed in wild-type mice administered IL-33 in the presence or absence of IFN-α.
“We further show that the STAT1 and STAT5 pathways in ILC2s are affected by IFN-α, and using a knockout system, we show that the regulatory effects of IFN-α are partially mediated by STAT1,” the researchers comment.
Finally, they confirmed that human pDCs also suppress ILC2s and respond to IFN-α, potentiating proapoptotic pathways and inhibiting stimulatory ones.
“Our findings shed a new light on the underlying mechanisms of regulation of ILC2s and ILC2-mediated asthma pathogenesis,” say Akbari and co-authors.
“Moreover, our findings have clear clinical implications in asthma control and management.”
By Lucy Piper
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