The lung immune system is uniquely adapted to sustain continuous exposure to environmental stimuli while avoiding excessive inflammation. Among lung-resident immune cells, alveolar macrophages are well recognized as key regulators of immune quiescence and tissue homeostasis under steady-state conditions. In contrast, the roles of dendritic cells (DCs), another population of resident immune cells, have received comparatively less attention, likely owing to their lower abundance within the lung tissue. Nevertheless, as professional antigen-presenting cells and central orchestrators of adaptive immunity, DCs are critically positioned to determine the balance between immune tolerance and activation in the lung. Recent studies have increasingly highlighted the contribution of lung DCs to the pathogenesis of inflammatory and neoplastic lung diseases, including allergy, asthma, and cancer. However, how DCs are positioned, conditioned, and functionally regulated under steady-state conditions remains incompletely understood. In this review, we focus on spatial organization, cellular interactions, and microenvironmental cues that shape lung DC behavior at steady-state and delineate how these homeostatic programs preserve immune tolerance while maintaining immune readiness.
T cell-based universal influenza vaccines aim to generate robust lung-resident memory CD8+ T cells (TRM), yet it remains unclear whether conserved Ags elicit equally protective TRM pools. We compared recombinant adenoviral vectors expressing the influenza A nucleoprotein (rAd/NP) or polymerase basic protein 1 (PB1). After intranasal immunization, both induced comparable magnitudes of respiratory Ag-specific CD8+ T cells, yet only rAd/NP provided 100% survival after lethal influenza challenge. This disparity reflected qualitative differences in the TRM pool; nucleoprotein (NP)-specific cells were predominantly CD103-CD49a+, a phenotype associated with superior cytotoxicity, whereas PB1-specific cells were mainly CD103+CD49a-. Furthermore, NP-specific CD8+ T cells showed 100-fold higher functional avidity and stronger lung-local CTL activity than PB1-specific cells. Our findings demonstrate that TRM quality-specifically phenotypic bias and functional avidity-rather than magnitude, are the primary determinants of vaccine-mediated protection. This study underscores the critical importance of Ag selection in optimizing T cell-based universal vaccine strategies.
Mitochondria have long been viewed as the "powerhouses" of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells-glycolysis, oxidative phosphorylation, or fatty acid oxidation-determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the "dual identity" of mitochondria in skin immunity-as both metabolic regulators and signaling sensors-will lay the foundation for developing precise metabolic immunomodulatory therapies.
Neutrophils serve host defense through phagocytic activity in acute kidney injury. However, excessive neutrophil activation drives tissue damage during systemic inflammation. NOD-like receptor family pyrin domain-containing 3 (NLRP3) has been reported to regulate neutrophil function in inflammatory conditions, but it remains unclear how NLRP3 modulates neutrophil function in the kidney. We investigated the role of NLRP3 in regulating neutrophil phagocytic activity and infiltration in the kidney. Nlrp3 knockout (KO) and Nlrp3 KO/lysozyme M-GFP mice were analyzed by time-lapse imaging and intravital imaging under naïve and LPS-treated conditions. Nlrp3 KO neutrophils exhibited enhanced motility and phagocytic activity against pHrodo+ Escherichia coli particles. The enhanced phagocytic activity was confirmed at both cellular and tissue levels in Nlrp3 deficient kidneys in vivo. Nlrp3 deficient kidneys showed increased neutrophil infiltration accompanied by upregulation of Cxcl2 and Cxcr2 and downregulation of Cxcl12 and Cxcr4 under naïve and LPS-treated conditions. Despite increased infiltration, Nlrp3 deficient kidneys under LPS treatment displayed reduced Il1b and Il6 expression and attenuated tissue damage. Collectively, these findings suggest that NLRP3 suppresses neutrophil effector function at the cellular level. At the tissue level, NLRP3 amplifies inflammatory tissue injury in the kidney.
