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Open research questions in IL-33, ST2, and ILC Pathways

33 unresolved questions extracted from the limitations and future-work sections of 157 IL-33, ST2, and ILC Pathways papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Abstract Type 1 innate lymphoid cells (ILC1) are abundant in the adult liver and are pivotal for immune surveillance and modulation, but the regulation of their maintenance and functionality remains underexplored.

    ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver · 2026 · DOI

  • Enhancing ALOX15—SPM signaling or restoring STING-dependent ALOX15 induction warrants exploration as a host-directed strategy to promote resolution in schistosomiasis.

    Alox15 diminishes inflammation by inducing STING and Type I Interferon production in response to schistosome eggs in dendritic cells 2259492 · 2026 · DOI

  • The IL-23/Th17 axis is a central driver of intestinal and spondyloarthritic inflammation, yet upstream regulatory mechanisms linking microbial signals to IL-23 production remain incompletely defined.

    Bioactive produced by Enterococcus Faecalis targets IL-23 signalling and protects against colitis and joint disease · 2026 · DOI

  • Eosinophils in allergic rhinitis harbor a substantial yet underrecognized immunoregulatory capacity that encompasses IL-10-mediated Treg crosstalk, TGF-b-driven immune tolerance, lipid mediator class-switching from CysLTs to SPMs, and func- tional heterogeneity between tissue-resident and inflammatory subsets.

    Eosinophils as immunoregulatory players in allergic rhinitis: beyond cytotoxicity · 2026 · DOI

  • Several open questions delineate the frontier of this field: (i) what is the relative proportion of rEos versus iEos in the healthy versus AR nasal mucosa, and how does this ratio change during AIT?; (ii) through what…

    Eosinophils as immunoregulatory players in allergic rhinitis: beyond cytotoxicity · 2026 · DOI

  • The author(s) declared that financial support was not received for this work and/or its publication. This review confirms that eosinophils occupy a central position in immune networks and, as such, being implicated in an increas- ingly diverse array of health and disease contexts. While further research on the roles of eosinophils in immune regulation is it appears that IL-4, IL-5 and IFN-g necessary and ongoing, pathways may be especially important in eosinophil-mediated immune regulation of diseases, including — but not limited to — homeostasis, cancer, respiratory, reproductive, vascular, gastroin- testinal, muscular and immune diseases. Although their roles are crucial, it appears that the microenvi- ronment of eosinophils is itself a key determinant of eosinophils’ immunological roles, whether pro- or anti-inflammatory, beneficial or detrimental, prognostically good or poor. Understanding the factors at work in the healthy eosinophilic microenvironment — and those that skew it in disease — is vital in order to devise effective treatments for eosinophil-associated diseases. It is due to their central role in immunity that treatment of eosinophil-based disor- ders must be targeted. For example, although IL-5 blocking mono- clonal antibody is successfully used in the treatment of eosinophilic asthma, this strategy also works to greatly reduce airway tissue, periphery and bone-marrow eosinophils. This approach, through down-regulation of eosinophil numbers and functions, places the organism at loss of the numerously beneficial, pro-inflammatory and anti-tumorigenic roles that eosinophils also have to offer, in the regulation of diseases such as cancer, tissue repair and respiratory diseases, in which eosinophilia is associated with a good prognosis. Ideally, taking advantage of the pioneering of asthma IL-5 blocking antibody, future treatment strategies should be rather more targeted to diseases-specific mediators in order to prevent indiscriminate eosinophil ablation. This ambitious aim, while simply stated, may Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

    The emerging roles of eosinophils in immune regulation in health and disease · 2026 · DOI

  • Skeletal muscles secrete a variety of cytokines in response to inflammatory stimuli such as lipopolysaccharide (LPS); however, the contributions of resident macrophages or other non-muscle cells to the secretory responses are not well understood.

    Resident myeloid-derived immune cells contribute to early lipopolysaccharide-induced cytokine secretion in mouse soleus muscle · 2026 · DOI

  • In ulcerative colitis (UC), impaired tolerogenic pathways result in exaggerated immune activation, epithelial dysfunction, and tissue damage; however, the contribution of BCs to disease pathogenesis remains unclear.

    An Altered Glycome Shapes IgA B-Cell Responses and Gut Immunity During Intestinal Inflammation · 2026 · DOI

  • The exact minimum effective concentration that recapitulates our observed suppressive ILC2 phenotype in vivo, remains to be determined, and will likely rely on a complex grouping of factors that take into account systems with endogenous melatonin rhythms (such that were absent in our studies both in vitro and in vivo with BALBc mice).

    Melatonin suppresses ILC2-driven airway hyperreactivity via glutathione-dependent metabolic reprogramming · 2026 · DOI

  • This study identified a central role for HDAC3 in stem cells for directing tuft cell differentiation. While F. prausnitizii and butyrate reduced tuft cells through this pathway, the outcome in the context of dynamic host and microbial signals may be more complex and remains to be elucidated. Furthermore, additional models will be needed to decipher the role of butyrate and HDAC3 in mature tuft cell function. HDAC3 impacts multiple transcriptional networks, so epigenetic regulation of a single gene is unlikely to be responsible for tuft cell programming. While ChIP-qPCR of bulk IECs suggest that HDAC3 may not alter basal H3K9Ac in the promoter of known regulators Pou2f3, Pou2af2, and Atoh1, global epigenetic analyses of intestinal stem cells will be necessary to identify enhancers and additional mechanisms. Examination of HDAC3 enrichment, in combination with these broader chromatin analyses, will enable discovery of direct regulatory sites across the genome of progenitor cells. Immunity. Author manuscript; available in PMC 2025 February 13. A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t Eshleman et al. Page 11 STAR METHODS RESOURCE AVAILABILITY Lead Contact—Further Information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Theresa Alenghat ([email protected]). Materials availability—Requests for reagents and resources generated in this study will be fulfilled by the lead contact. Data and code availability—Sequencing data has been deposited at GEO and is publicly available. Accession numbers are listed in the key resource table. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. EXPERIMENTAL MODEL AND STUDY PARTICIPANT DETAILS Mice.—Conventionally-housed C57BL/6J mice were purchased from Jackson Laboratories and maintained in our specific-pathogen free colony at Cincinnati Children’s Hospital Medical Center (CCHMC). Germ-free (GF) mice were maintained in flexible isolators in the CCHMC Gnotobiotic Mouse Facility, fed autoclaved feed and water, and monitored for absence of microbes. HDAC3FF were generated as previously described57, and crossed to C57BL/6J-Villin-Cre58 (HDAC3ΔIEC), tamoxifen-inducible Villin-Cre59 (HDAC3ΔIEC-IND), and tamoxifen-inducible Lgr5GFP-ERT2Cre60 (HDAC3ΔLGR5) mice. Spry2 floxed mice (MMRRC 11469) were crossed to C57BL/6J-Villin-Cre to generate Spry2ΔIEC mice as previously described.35 Sex- and age-matched littermate controls were used for all studies. Mice were housed up to 4-per cage in a ventilated cage system in a 12-h light/dark cycle, with free access to water and food. All mouse studies were conducted with approval by Animal Care and Use Committees at CCHMC.

    Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity · 2024 · DOI

  • Additional functional studies are needed to decipher the role of multiple cell types described in this atlas. For instance, we foresee that further functional characterization of the slan-like compartment will unravel the specialized functions of the four myeloid subsets we described here. Because the markers of our slan-like clusters partially overlap with macrophage states reported in other efforts, future studies will unequivocally clarify whether slan-like represents a distinct myeloid cell type. Also, further experimental evidence is needed to disentangle the role of the SIX5 TF in PC lineage commitment. While current atlases of healthy human organs and tissues focus on the analysis of mostly transcriptional data, the presented atlas integrated five modalities, including spatially resolved transcriptional profiling. However, currently available ST technologies for transcriptome-wide profiling do not provide bona fide single-cell resolution and require capture site deconvolution to predict cell-type location by integrating single-cell and ST datasets, or analysis must be limited to signature and marker gene visualization.

    An atlas of cells in the human tonsil · 2024 · DOI

  • </ns4:p> <ns4:p> <ns4:bold>Conclusions</ns4:bold> : Together, these data provide new insight into ILC composition in different tissues in both WT and genetically modified mice where key costimulatory pathways are genetically deleted, providing a useful resource for further research into ILC biology.

    Characterisation of innate lymphoid cell populations at different sites in mice with defective T cell immunity · 2018 · DOI

  • Group 2 innate lymphoid cells contribute to cutaneous immune homeostasis and type 2 immune responses, yet the mechanisms governing their development and functional diversification remain incompletely understood.

    RAG1 deficiency durably alters dermal group 2 innate lymphoid cells and modifies contact hypersensitivity · 2026 · DOI

  • Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown.

    Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis · 2026 · DOI

  • Pulmonary immunity in the human distal respiratory airways is essential for lung function but remains poorly explored, mainly due to limited physiologically relevant models.

    hPSC-Derived Distal Lung Organoids Reveal Respiratory Airway Secretory Cells Acting as Immune Sentinels in Human Distal Airways · 2026 · DOI

  • IL-17A has been implicated in airway inflammation and fibrosis, but its role in AR and the underlying mechanisms remain incompletely understood.

    IL-17A activates the PI3K/AKT/mTOR pathway to regulate bronchial fibroblast autophagy-mediated airway remodeling: evidence from conditional IL-17RA-deficient mice · 2026 · DOI

  • We also discuss emerging mechanistic and therapeutic insights into how diet, food‐derived molecules or treatments shape mucosal immunity, and highlight key knowledge gaps that warrant further investigation to clarify how disruptions in these interactions contribute to allergic sensitization.

    Diet–Microbiome–Immune Interactions at the Gut Mucosa in Food Allergy: Mechanisms, Gaps, and Therapeutic Implications · 2026 · DOI

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33 open questions have been extracted from the limitations and future-work passages of 157 IL-33, ST2, and ILC Pathways papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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