T cell subsets play distinct roles in the immune response, and their balance is crucial for immune homeostasis. Luteolin has been shown to affect the differentiation and proportions of T cell subsets (38–41). It was reported that luteolin promotes the differentiation and function of regulatory T cells (Tregs) (38, 41). In a cecal ligation and puncture (CLP)-induced acute lung injury (ALI) mouse model, luteolin alleviated lung injury, suppressed uncontrolled inflammation, and upregulated levels of interleukin-10 (IL-10) in serum and bronchoalveolar lavage fluid (BALF). It increased the frequency of CD4 ⁺ CD25 ⁺ Foxp3 ⁺ Tregs in peripheral blood and in splenic mononuclear cells of ALI mice. In vitro, luteolin significantly induced the differentiation of Tregs (38). Zhang et al. also found that, in a CLP-induced ALI mouse model, luteolin activated Tregs to promote IL-10 expression and alleviated caspase-11-dependent pyroptosis in sepsis-induced lung injury. Depleting Tregs reversed the beneficial effects of luteolin on lung injury, indicating the importance of Tregs in the luteolin-mediated protective effect (39). Kim and colleagues demonstrated that luteolin increased the number of CD4⁺CD25⁺ Tregs in vitro, with elevated levels of transforming growth factor-β1 (TGF-β1) and Foxp3 messenger ribonucleic acid (mRNA) expression, and the transfer of these Tregs into ovalbumin (OVA)-sensitized mice (a murine model of airway inflammation) reduced airway hyper-responsiveness, eosinophil recruitment, and T helper 2 (Th2) cytokine expressions, and increased interferon-γ (IFN-γ) production (40). Luteolin can also regulate the Th17/Treg balance. In allergic rhinitis (AR) mouse models, luteolin restored the Th17/Treg balance, reducing sneezing frequency, nasal mucosal thickness, and levels of anti-OVA-IgE, autophagy-related factors (Beclin1, LC3II/LC3I), IL-17A, and retinoic acid receptor-related orphan receptor γt (RORγt), while increasing anti-OVA-IgG2a, IL-10, and Foxp3 levels (41, 42). In an AR rat model, luteolin promoted the downregulated levels of Th1-type cytokines (IL-2, IFN-γ) and suppressed the upregulated levels of Th2-type cytokines (IL-4, IL-5, IL-13), indicating its role in modulating the Th1/Th2 balance (43). Furthermore, luteolin could also affect the follicular helper T (Tfh)/follicular regulatory T (Tfr) balance (17). It reduced thyroxine T4 and thyrotropin-receptor antibody (TRAb) levels and facilitated recovery from thyroid damage in Graves disease (GD) mice. It effectively alleviated oxidative stress and restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, along with regulating related mRNA levels of IL-21, Bcl-6, and Foxp3 (17). Therefore, luteolin has a significant impact on the balance and function of T cell subsets, especially in promoting Treg differentiation and regulating the Th17/Tregs, Th1/Th2, and Tfh/Tfr balances, which is beneficial for maintaining immune homeostasis in various disease conditions.

T cell activation and proliferation are key events in immune responses, and inappropriate activation can lead to autoimmune diseases or excessive immune reactions (44). Luteolin has been shown to inhibit antigen-specific T cell responses (45). Verbeek and co-workers evaluated the inhibitory effects of various flavonoids on antigen-specific proliferation and IFN-γ production by human (specific for alpha B-crystallin) and murine (specific for encephalitogenic proteolipid protein [PLP] peptide) autoreactive T cells. The flavones apigenin and luteolin were strong inhibitors of both murine and human T cell responses, with antigen-specific IFN-γ production reduced more than T cell proliferation. This suggests that luteolin can target the potentially pathogenic functions of autoreactive T cells involved in autoimmune diseases (45). Moreover, luteolin suppressed T cell activation in specific models (46). Kempuraj et al. found that luteolin pretreatment inhibited myelin basic protein-induced human mast cell activation and mast cell-dependent stimulation of Jurkat T cells. In this study, mast cells activated Jurkat cells, and this interaction was inhibited by luteolin, suggesting its potential in treating autoimmune diseases related to T cell activation (46). The effect of luteolin in psoriasis was previously explored in a mouse model, and the results showed that it alleviated skin tissue lesions and symptoms. The underlying mechanisms involved suppression of IFN-γ secretion and reductions in the proportion of Th1/Th2 and Th17/Treg cells, and inhibition of increases in Th1 and Th17 cells in the peripheral blood, indicating its role in suppressing T cell activation and function in the context of psoriasis (13). These studies indicate that luteolin can effectively inhibit T cell activation and proliferation in different models, which may be useful in treating autoimmune and other immune-related diseases.

T cells are crucial for the body’s defenses against tumors and infectious agents. Luteolin can enhance the antitumor and anti-infective functions of T cells (47–51). Tian et al. investigated luteolin as an antitumor vaccine adjuvant in a B16F10 mouse model and found that it activated the PI3K-AKT pathway in antigen-presenting cells (APCs), induced the activation of APCs, enhanced cytotoxic T lymphocyte (CTL) responses, and inhibited tolerogenic T cell responses. The survival rate of tumor-bearing mice was significantly improved by the adoptive transfer of CD8⁺ T cells from luteolin-immunized mice (47). In recent studies, luteolin was reported to inhibit the proliferation and invasion of colon and lung cancer cells, directly or by enhancing T cell-mediated killing pathways (48, 51). When combined with activated CTLs, it upregulated CD25 and CD69 expression on effector cells, increased the secretion of IL-2, tumor necrosis factor-α (TNF-α), and IFN-γ in vitro, and significantly curbed subcutaneous tumor growth and extended the survival time of tumor-bearing mice in vivo (48). The antitumor effect of luteolin was also investigated in H22 tumor-bearing mice, in which luteolin effectively constrained tumor-cell growth and enhanced T cell activation, cell chemotaxis, and cytokine production. It maintained a high ratio of CD8⁺ T lymphocytes in the spleen, peripheral blood, and tumor tissues, restored the cytotoxicity of tumor-infiltrating CD8⁺ T lymphocytes, and enhanced the antitumor effect when combined with the PD-1 inhibitor (49). Moreover, evidence shows that luteolin could boost the anti-infective immunity. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Singh et al. demonstrated that, as a plant-derived Kv1.3 K⁺ channel inhibitor, luteolin promoted TCM cells by selectively inhibiting TEM cells in mice vaccinated with Bacillus Calmette-Guérin (BCG), significantly enhancing BCG vaccine efficacy (50). The same group subsequently showed that, when administered with isoniazid, luteolin promoted anti-tuberculosis (TB) immunity, reduced TB treatment duration, and prevented disease relapse. It also enhanced long-term anti-TB immunity by promoting TCM cell responses and the activity of NK and natural killer T (NKT) cells (52). Therefore, luteolin can promote CTL activation and proliferation in the antitumor context and modulate T cell memory subsets and other immune cells to enhance immune response against infectious diseases.

Macrophages dynamically polarize into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, regulated by multiple signaling pathways. STAT3 activation promotes pro-inflammatory cytokine production, while STAT6 drives M2 polarization and anti-inflammatory mediator release; their reciprocal regulation forms a core inflammatory balance axis (61). Peroxisome proliferator-activated receptor γ (PPARγ) not only directly enhances M2 polarization (synergizing with STAT6) but also intersects with the TLR4-NF-κB pathway by suppressing IκB phosphorylation. Together, these molecules and their cross-talk contribute to the restoration of immune homeostasis (62). Luteolin treatment could reduce M1 markers (iNOS, IL-1β, TNF-α, CD86) and upregulate M2 markers (Arginase 1, IL-10, IL-13, CD163, CD206) in LPS/IFN-γ-stimulated macrophages via STAT3 inhibition and STAT6 activation (63). Similarly, Yang et al. found that luteolin suppressed inflammation in DSS-induced colitis in vivo and promoted M2 polarization by activating the AMP-activated protein kinase (AMPK)/PPARγ pathway, reducing M1-associated cytokines (TNF-α, IL-6, and IL-1β) (14). This effect is further corroborated in THP-1-derived macrophages, where luteolin upregulated the circular RNA hsa_circ_0001326 to suppress M1 markers and enhance M2 markers (64). Collectively, these findings suggest luteolin reprograms macrophages to an anti-inflammatory phenotype through STAT and PPARγ-dependent pathways.

Luteolin potently suppresses pro-inflammatory signaling cascades in macrophages. Xue et al. reported that luteolin blocked NF-κB activation by inhibiting IKKα/β phosphorylation, thereby reducing pro-inflammatory cytokines (IL-6, TNF-α) in LPS-stimulated macrophages and ameliorating DSS-induced colitis (65). Zou et al. extended these findings; luteolin was found to exert a preventive effect on THP-1 macrophage pyroptosis by inhibiting NLRP3 inflammasome activation, largely by suppressing ROS production via nuclear factor erythroid 2-related factor 2 (Nrf2) activation as well as NF-κB inactivation. These findings suggest that luteolin has the potential to prevent pyroptosis by regulating the Nrf2-NF-κB crosstalk (66). Additionally, luteoloside reduced hepatic fibrosis by activating the TLR2/TLR4 axis, which suppressed NLRP3 inflammasome activation, secretion of pro-inflammatory cytokines (IL-1β, IL-6), and extracellular matrix deposition in macrophages and hepatic stellate cells (67). Analogously, luteolin attenuated lupus nephritis by inhibiting the hypoxia-inducible factor-1α (HIF-1α) pathway in macrophages, thereby reducing oxidative stress, inflammatory mediator release (e.g., ROS, TNF-α), and renal damage (68). These studies converge on luteolin’s ability to dampen multiple inflammatory axes, including NF-κB, NLRP3, and TLR pathways, highlighting its potential as a therapeutic agents for autoimmune, inflammatory, and fibrotic diseases.

Luteolin exerts multifaceted effects on macrophage functional activities, including phagocytosis and chemotaxis (65, 69, 70). It was reported that luteolin enhanced macrophage phagocytosis by blocking CD47 pyroglutamation via glutaminyl-peptide cyclotransferase-like protein (isoQC), disrupting the “don’t eat me” signal in tumor cells (69). Luteolin also suppressed NLRP3 inflammasome activation and TLR4/NF-κB signaling in macrophages, reducing pro-inflammatory cytokine release and promoting apoptotic cell clearance in fibrosis and sepsis (65). Regarding chemotaxis, luteolin inhibited CCL2-induced macrophage migration by antagonizing IKKα/β phosphorylation and NF-κB nuclear translocation, reducing inflammatory infiltration in colitis (65). In periodontitis, luteolin ameliorated periodontal inflammation and bone loss by modulating mitochondrial dynamics, promoting M2 macrophage polarization, and suppressing the JAK2/STAT3 signaling pathway (71). Collectively, these findings position luteolin as a promising therapeutic for macrophage-driven diseases by enhancing phagocytic clearance while dampening chemotaxis and inflammation.

Luteolin often acts synergistically with other compounds to augment anti-inflammatory effects. Notably, in LPS-stimulated RAW264.7 macrophages, the expression of ROS, NO, TNF-α, IL-6, and IL-1β was significantly increased, which was reversed by the combination of luteolin and paeoniflorin via suppression of the NF-κB/MAPK signaling pathway (72). Similarly, in hepatitis B virus infection, luteolin enhanced cGAS-STING activation in macrophages when paired with schisandrin C to control viral replication (73). These combinatorial strategies highlight luteolin’s versatility in therapeutic regimens.

Neutrophils contribute to inflammation through oxidative stress, protease release, and adhesion molecule-mediated tissue infiltration. In inflammatory arthritis models, luteolin inhibited neutrophil superoxide anion generation, ROS production, and NET formation by targeting the Raf1/mitogen-activated protein kinase kinase-1 (MEK-1)/extracellular signal-regulated kinase (ERK) signaling axis, thereby reducing leukocyte infiltration and paw edema (77). Similarly, in an endotoxin-induced ALI model, luteolin attenuated neutrophilic inflammation by scavenging ROS, reducing myeloperoxidase activity, and inhibiting MAPK/NF-κB-mediated secretion of TNF-α and intercellular adhesion molecule-1 (ICAM-1) (78). Mechanistically, luteolin can inhibit cyclic adenosine monophosphate (cAMP)-phosphodiesterases (PDEs) activity and the expression of lymphocyte function-associated antigen-1 in neutrophils (79). Moreover, luteolin metabolites, such as luteolin monoglucuronide, are hydrolyzed by beta-glucuronidase released from neutrophils at inflammatory sites to yield free luteolin, which suppresses TNF-α-induced ICAM-1 expression and interferes with adhesion between neutrophils and endothelial cells (80). Thus, these findings indicate that luteolin can mitigate neutrophil-driven oxidative stress and inflammation by targeting redox signaling, adhesion molecules, and inflammatory mediator release.

Neutrophils, key effector cells in acute inflammation, contribute to tissue damage through chemotaxis, respiratory burst, and delayed apoptosis. Luteolin modulates neutrophil functions via distinct signaling mechanisms. In LPS-induced ALI, luteolin attenuated neutrophil chemotaxis and respiratory burst by inhibiting MEK/ERK and PI3K/AKT phosphorylation, thereby reducing leukocyte infiltration and protein extravasation (12). Similarly, luteolin blocked Fcγ receptor-mediated respiratory burst in granulocytes by targeting downstream signaling cascades, though this effect did not translate to blister suppression in pemphigoid models, suggesting context-dependent efficacy (81). Mechanistically, luteolin induced neutrophil apoptosis through proteasomal degradation of Mcl-1, a pro-survival Bcl-2 family protein, thereby overcoming survival signals from LPS or granulocyte-macrophage colony-stimulating factor (GM-CSF). This apoptotic effect is caspase-dependent and enhanced in inflammatory microenvironments, positioning luteolin as a pro-resolution agent (82). Taken together, these studies suggest luteolin’s multifaceted regulation of neutrophil signaling, spanning MAPK/PI3K pathways, Fcγ receptor responses, and apoptotic machinery.

Neutrophilic inflammation drives tissue damage in diseases such as lung fibrosis, asthma, and periodontitis, making modulation of neutrophil activation a therapeutic priority. Luteolin demonstrates efficacy across these contexts through distinct mechanistic pathways. In bleomycin-induced lung fibrosis, luteolin reduced neutrophil infiltration and inflammatory cytokines (TNF-α, IL-6) in the BALF while inhibiting TGF-β1/Smad3-mediated myofibroblast differentiation and epithelial-to-mesenchymal transition (83). This dual anti-inflammatory and antifibrotic effect translates to reduced collagen deposition and preserved lung architecture (83). In neutrophilic asthma models, luteolin suppressed IL-36γ secretion and MAPK/IL-1β signaling, attenuating neutrophilic airway inflammation and hyperresponsiveness (84). Mechanistically, luteolin blocked LPS-induced IL-36γ upregulation in bronchial epithelial cells, thereby disrupting the pro-inflammatory feedback loop, thus reducing the secretion of inflammatory factors and alleviating the inflammatory response (84). In periodontitis, luteolin mitigated LPS-induced alveolar bone loss by inhibiting neutrophil infiltration, NF-κB activation, and the expression of pro-inflammatory enzymes (iNOS, COX-2) and cytokines (IL-6, TNF-α), while preserving collagen integrity (85). Collectively, these studies highlight luteolin’s ability to target neutrophilic inflammation through redox regulation, cytokine modulation, and extracellular matrix preservation, positioning it as a promising candidate for neutrophil-driven inflammatory disorders.

Numerous studies have demonstrated that luteolin can reduce eosinophil infiltration in allergic models (87–89). In murine models of allergic asthma, luteolin reduced eosinophil and neutrophil infiltration in BALF, concomitant with decreased levels of IL-4, IL-5, and IL-13 in lung homogenates (87). This effect was paralleled in allergic nasal inflammation, where luteolin attenuated eosinophilic infiltration, mucus hypersecretion, and serum house dust mite-specific IgE, while downregulating CD4⁺ IL-4-secreting T cells via inhibition of STAT6/GATA3 signaling (88). It suppressed prostaglandin E2 (PGE2) production and Th2 cytokine transcription in both in vitro and in vivo settings (88). In OVA-induced asthma, luteolin-7-O-glucoside (L7G), a bioactive derivative, dose-dependently reduced eosinophil infiltration and PGE2 levels in BALF, while inhibiting IL-4, IL-5, and IL-13 mRNA expression (89). Lee et al. evaluated the inhibitory effects of luteolin on the immediate-phase asthmatic response (IAR) and the late-phase asthmatic response (LAR) to aerosolized OVA exposure in conscious OVA-sensitized guinea pigs. The results showed that the anti-asthmatic effect of luteolin in IAR and LAR likely reflects inhibition of eosinophil recruitment that underlies the subsequent pathological changes and suppression of biochemical mediators such as histamine, phospholipase A2, and eosinophil peroxidase in the asthmatic lung, thereby reducing antigen-induced bronchoconstriction (90). These effects were attributed to luteolin’s ability to interfere with eosinophils’ recruitment and activation, thereby disrupting the inflammatory cascade.

Luteolin modulates eosinophil-driven inflammation by targeting Th2 cytokines and transcription factors. Park et al. reported that luteolin-4’-O-glucoside suppressed IL-5 bioactivity, a key eosinophil chemoattractant and growth factor, with an IC₅₀ of 3.7 μM (91). A recent study revealed that luteolin reduced IL-4, IL-5, and IL-13 levels in mice with eosinophilic chronic rhinosinusitis (ECRS), restoring olfactory sensory neurons via TLR4/NF-κB pathway inhibition (18). Mechanistically, luteolin inhibits STAT6 phosphorylation and GATA3 expression, both critical for Th2 differentiation (18). In allergic rhinitis models, luteolin decreases CD4⁺ IL-4-secreting T cells by downregulating STAT6/GATA3 signaling, thereby reducing eosinophil infiltration and mucus hypersecretion (88). This finding aligns with another study where luteolin induced CD4⁺CD25⁺ Tregs expressing Foxp3 and TGF-β1, counteracting Th2 dominance and reducing eosinophil recruitment (40). Accordingly, luteolin’s dual actions—suppressing Th2 cytokine secretion and promoting Tregs—offer a multifaceted approach to allergic inflammation.

Luteolin exhibits robust antioxidant and anti-apoptotic properties in eosinophilic disorders by targeting redox imbalance and apoptotic signaling. In the ECRS mouse model, luteolin reduced oxidative stress in olfactory sensory neurons (OSNs) by increasing the activities of antioxidant enzymes (Superoxide Dismutase [SOD], catalase [CAT], glutathione peroxidase [GSH-Px]) and decreasing malondialdehyde (MDA), while attenuating OSN apoptosis by Bcl-2 upregulation and caspase-3/9 inhibition. The anti-apoptotic effects of luteolin on OSNs were reversed by LPS-induced TLR4/NF-κB activation, suggesting that luteolin exerts its anti-apoptotic effects by inhibiting TLR4/NF-κB (18). These effects were validated in human olfactory epithelial cells, where luteolin reversed LPS-induced ROS generation and apoptosis (18). The dual antioxidant and anti-apoptotic actions of luteolin in eosinophilic inflammation highlight its therapeutic potential for diseases marked by oxidative damage and excessive cell death.