Estrogen receptor alpha signaling increases ILC2-mediated allergic airway inflammation

Abstract

RATIONALE: The purpose of this study was to determine whether conventionally used ILC2 markers, ST2 and CD127, are sufficient to include all Th2-cytokine producing ILCs. We hypothesized that ST2-and CD127-negative ILC2 populations exist in mouse lung and that these nontraditional populations might be activated by the clinically relevant fungal allergen Alternaria, a known potent inducer of IL-33. METHODS: Mice were challenged intranasally with Alternaria alternata for three consecutive days, and 24 hours after the last challenge brochoalveolar lavage fluid and lungs were harvested for flow cytometric analysis, ELISA, and lung section staining. ILCs were identified by flow cytometry as CD45+Lineage-Thy1.2+ lymphocyte-sized cells and were separated into four subsets based on ST2 and CD127 expression. Intracellular cytokine and transcription factor staining were performed on the ILC populations. RESULTS: Th2 cytokine-producing ILCs were identified in all four subpopulations, regardless of ST2 and CD127 expression, as evidenced by high GATA-3, IL-5, IL-13 and ILC2 surface marker expression. Further, ILC2 cytokines and surface markers were upregulated following Alternaria challenge, irrespective of ST2 and CD127 expression. The four ILC subpopulations were also found in RAG2 knockout mice, which is supportive of their presence being T-cell independent. Some of the unconventional ILC2s also produced IFNg and IL-17A suggesting the existence of ILC2 plasticity in these populations. CONCLUSIONS: Unconventional ST2-and CD127-negative ILC2 populations exist in mouse lung and are further induced by Alternaria. Thus, future mouse ILC2 investigations should be aware of ILC2 populations that do not express ST2 and CD127.

The Rising Era of “Immunoporosis”: Role of Immune System in the Pathophysiology of Osteoporosis

“…A study demonstrated that ERα signaling via promoting secretion of IL-33 cytokine augments the proliferation and activation of ILC2. 43 Moreover, it has been observed that the adoptive transfer of IL-4 + /IL-13 + ILC2 in the initiation phase of arthritis significantly attenuated inflammatory bone loss in both serum-induced arthritis (SIA) and collagen-induced arthritis (CIA) mice models, on the contrary IL-4 − /IL-13 − ILC2 failed to do the same. 44 Importantly, at later time points, even adoptive transfer of IL-4 + /IL-13 + ILC2 failed to suppress arthritis in SIA and CIA mice models.…”