Neutrophil Subsets May Explain the Stubborn Form of Allergic Rhinitis That Steroids Fail to Treat

Allergic rhinitis has long been told as an eosinophil story. Sneezing, itching, and a runny nose are attributed to IgE antibodies, type 2 inflammation, and a flood of eosinophils into the nasal lining, and the standard treatments—intranasal corticosteroids and antihistamines—are built squarely around that narrative. But a substantial minority of patients do not fit the script. Their nasal secretions teem with neutrophils rather than eosinophils, their symptoms shrug off conventional therapy, and their inflammation looks closer to the type 2-low, corticosteroid-refractory patterns seen in a subset of asthmatics. A new mini review in Frontiers in Allergy argues that the key to this neglected endotype may lie in one of immunology’s most surprising recent rediscoveries: the neutrophil is not a single, short-lived foot soldier, but a diverse family of cells with radically different—and sometimes opposite—functions.

The review, authored by Pengyuan Yu, Feihu Wu, and colleagues at institutions across China, synthesizes evidence on low-density neutrophils, or LDNs, and advances a hypothesis that could reshape how clinicians think about treatment-resistant rhinitis. Neutrophils make up 50 to 70 percent of circulating leukocytes and were historically dismissed as terminally differentiated antimicrobial effector cells. Contemporary work has demolished that view. Neutrophil identity, the authors emphasize, is shaped by anatomical niche, inflammatory stimulus, microbial exposure, metabolic state, sex, and developmental stage. Neonatal neutrophils, for instance, form defective neutrophil extracellular traps and run distinct functional programs compared with adult cells. The compartment is plastic, and its subsets can either fan inflammation or suppress it.

Low-density neutrophils are defined operationally rather than by surface markers: they are the cells that float in the buoyant fraction during density-gradient centrifugation, instead of settling with ordinary dense neutrophils. Far from being a centrifugation artifact, this population expands across autoimmune disease, infection, cancer, and cardiovascular illness, and it harbors two functionally opposed poles. At one end sit low-density granulocytes, or LDGs, which are pro-inflammatory and intrinsically primed to release neutrophil extracellular traps—web-like structures of extracellular DNA studded with myeloperoxidase and neutrophil elastase that link to tissue injury and thrombosis. At the other end sit polymorphonuclear myeloid-derived suppressor cells, or PMN-MDSCs, which dampen T-cell proliferation through arginase-1, reactive oxygen species, and nitric oxide. Crucially, the same surface phenotype—CD11b-positive, CD15-positive, CD33-positive, CD66b-positive, CD14-negative, with variable LOX-1 expression—can map onto either behavior depending on disease context.

Systemic lupus erythematosus provides the most instructive parallel. In lupus, LDGs are not suppressive at all: they produce interferon-gamma and tumor necrosis factor-alpha, promote Th1 responses, and activate T cells despite carrying LOX-1, a marker often treated as a signature of suppressor cells. LDN identity, in other words, is not fixed but decoded by niche and activation state. That duality is precisely why the authors find the compartment so compelling in allergic rhinitis, where neutrophils might simultaneously restrain and amplify inflammation. The review is careful, however, to keep two classification schemes distinct: density-defined LDNs and phenotypically defined subsets such as CD16-high CD62L-dim activated neutrophils or LOX-1-positive neutrophils may or may not co-purify in the low-density fraction, and whether they do so in rhinitis patients has not been tested.

The human evidence in allergic rhinitis itself is sparse but provocative. In 2017, Arebro and colleagues showed that during pollen season, patients have elevated neutrophils in blood, nasal biopsies, and nasal lavage, with the activated CD16-high CD62L-dim subset predominating in nasal tissue and end-state CD16-dim CD62L-dim cells accumulating in lavage fluid. Those activated neutrophils primed T cells and enhanced eosinophil migration in vitro, pointing to an active immunomodulatory role rather than passive infiltration. More recently, Deng and co-workers characterized circulating LOX-1-positive neutrophils, defined as CD14-negative CD11b-positive CD15-positive LOX-1-positive cells, and found them significantly increased in the peripheral blood of allergic rhinitis patients. Unlike classical suppressor cells, these cells promoted CD3-positive T-cell proliferation and pro-inflammatory cytokine release, and their abundance correlated with neither IgE levels, age, nor sex—an independence from classical type 2 sensitization that hints at a genuinely non-type 2 pathway.

The idea that allergy reshapes neutrophil density is older than one might expect. Back in 1990, Miyagawa and colleagues demonstrated that allergic subjects harbor a greater proportion of lower-density neutrophil fractions, and that platelet-activating factor and granulocyte-macrophage colony-stimulating factor can convert neutrophil density in vitro—implying that soluble mediators in the allergic milieu can generate buoyant, LDN-like cells. Whether neutrophil extracellular traps operate in the allergic nasal niche is far less settled. A dedicated analysis of upper-airway secretions detected clear NET structures in infectious rhinitis but found none in allergic rhinitis, where only small amounts of non-NET extracellular nucleic acids appeared. Yet a 2026 study in ovalbumin- and house-dust-mite mouse models showed that interferon-induced ISG-high nasal neutrophils release NETs that promote disease, and that clearing nasal commensal viruses with ribavirin or blocking interferon sensors suppressed NET activity and alleviated symptoms. NET release is thus established in experimental allergic rhinitis but remains unconfirmed in human secretions.

The mechanistic heart of the review is neutrophil–T cell crosstalk, presented candidly as a candidate mechanism rather than a proven one. Activated CD16-high CD62L-dim neutrophils from rhinitis patients prime T cells and augment eosinophil recruitment, while LOX-1-positive neutrophils directly drive T-cell proliferation and cytokine production. In lupus, LDGs break T-cell anergy and favor Th1 responses. A regulatory counterweight also exists: a CD11b-bright CD62L-dim CD16-bright subset suppresses T-cell proliferation through Mac-1-dependent, hydrogen-peroxide-mediated mechanisms, and PMN-MDSCs attenuate allergic airway inflammation in mice by restraining group 2 innate lymphoid cells. In experimental asthma, granulocytic myeloid-derived suppressor cells track with elevated Th17 cells. The net inflammatory output in the nose may therefore reflect the balance between pro-inflammatory LDGs and suppressive PMN-MDSCs—and because the pro-inflammatory signals skew toward type 1 and type 17 pathways independent of IgE and eosinophils, they offer a plausible substrate for a neutrophil-rich endotype that escapes type 2-directed therapy.

The translational implications are concrete. Nasal cytology already separates the eosinophilic endotype from the neutrophilic one, in which neutrophils constitute at least 90 percent of inflammatory cells, and prospective data show that neutrophilic patients gain limited relief from intranasal corticosteroids plus antihistamines but improve substantially when switched to clarithromycin, exploiting the macrolide’s anti-neutrophilic immunomodulatory properties. As candidate biomarkers, the authors highlight nasal cytology and circulating LOX-1-positive neutrophil counts, both needing prospective validation; NET burden remains exploratory given its unconfirmed presence in allergic secretions. Adjacent findings in chronic rhinosinusitis with nasal polyps illustrate what might transfer: the NET-to-neutrophil ratio independently predicts postoperative refractoriness in the neutrophilic endotype, and DNase I or the elastase inhibitor sivelestat reduces polyp formation by blocking NET-driven basal-cell hyperplasia—though these are sinusitis data, not rhinitis data.

Therapeutic strategies, the authors argue, should be matched to the LDN compartment rather than to neutrophils in general. Anti-LOX-1 is the only approach aimed at a marker enriched on pro-inflammatory cells and could blunt T-cell activation without broad immunosuppression. NET inhibition with DNase I addresses the LDG-prone phenotype where traps are operative. Macrolide immunomodulation may rebalance the LDG–MDSC axis, though its effect on subsets is untested. Niche-targeted options include the nasal microbiome—commensal Staphylococcus aureus can modulate IL-33-dependent type 2 responses—and recruitment blockade, since pollen and cat-dander allergens drive innate neutrophil influx through Toll-like receptor 4 and CXCR2 signaling, with CXCR2 antagonism abrogating sensitization in mouse models. The authors stress that IL-33 is a type 2 epithelial alarmin with no established link to LDNs, so it is not presently a neutrophil-directed target.

What emerges is a research agenda rather than a finished story. Standardized gating strategies for human LDN subsets are lacking, hobbling cross-study comparison; whether CD16-high CD62L-dim or LOX-1-positive cells co-purify with the low-density fraction in rhinitis is untested; longitudinal cohorts are needed to determine whether LDN profiles predict chronicity or treatment response; and interventional trials of neutrophil-directed agents in molecularly defined neutrophilic patients are essentially absent. The authors’ central contention is that the field must treat neutrophils—not merely eosinophils—as candidate endotype determinants in allergic rhinitis. If the hypothesis holds, the stubborn, steroid-refractory form of the disease may finally acquire a molecular identity, a measurable biomarker, and a rational route to therapy.

Subject of Research: Low-density neutrophil heterogeneity and the non-type 2 endotype of allergic rhinitis

Article Title: Low-density neutrophil subsets in allergic rhinitis: heterogeneity and an emerging hypothesis for the non-type 2 endotype

Article References: Yu, P., Wu, F., Chen, Y., Li, Y., Zhang, X., Ruan, Y., Liu, G., & Han, X. (2026). Low-density neutrophil subsets in allergic rhinitis: heterogeneity and an emerging hypothesis for the non-type 2 endotype. Frontiers in Allergy, 7, Article 1934796. https://doi.org/10.3389/falgy.2026.1934796

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1934796

Keywords: allergic rhinitis, low-density neutrophils, neutrophil heterogeneity, LOX-1, neutrophil extracellular traps, non-type 2 inflammation, myeloid-derived suppressor cells, nasal cytology, macrolide therapy, endotypes, T-cell crosstalk, CXCR2