Although heated tobacco products (HTPs) reduce combustion-derived toxicants, increasing evidence indicates that they still induce adverse biological effects whose mechanisms remain poorly understood. We previously showed that HTP exposure impairs, whereas conventional cigarette (CC) exposure exacerbates, neutrophil influx into the inflamed synovium of mice with antigen-induced arthritis (AIA). Here, we investigated the effects of HTP vapor, CC smoke, and vaporized nicotine on neutrophil production and function. Naive and AIA mice and bone marrow (BM)-derived neutrophils were exposed to HTP vapor, CC smoke, or vaporized nicotine. Exposures were carried out in nicotine-equivalent model conditions. In vivo, CC exposure enhanced granulopoiesis, whereas HTP exposure impaired this process, as determined by the numbers of blast cells, immature neutrophils, and mature segmented neutrophils in the BM. In contrast, nicotine exposure increased the numbers of blast cells and band neutrophils and reduced mature circulating neutrophils; nonetheless, it did not alter neutrophil recruitment into the inflamed joint cavity. In BM-derived neutrophils, HTP vapor, CC smoke, and nicotine differentially affected neutrophil function. All exposures increased reactive oxygen species production. CC smoke increased ionomycin-induced extracellular DNA release, whereas both HTP vapor and CC smoke impaired chemotaxis. In contrast, nicotine enhanced neutrophil migratory capacity. STAT3 signaling was modulated following CC smoke and nicotine exposure but not HTP vapor. Together, these in vivo and in vitro findings demonstrate that CC smoke, HTP vapor, and nicotine differentially regulate neutrophil biology. Furthermore, these suggest that other constituents besides nicotine contribute substantially to HTP-induced immunotoxicity, providing mechanistic evidence that these products directly interfere with innate immune responses under inflammatory conditions.

PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) is a rare autosomal dominant autoinflammatory disorder caused by mutations in the PSTPIP1 gene. In pediatric patients, arthritis often precedes cutaneous manifestations by several years, leading to frequent misdiagnosis as septic arthritis. Treatment is challenging, with IL-1 inhibitors being the most pathophysiology-based first-line therapy, but their accessibility is limited by high costs. We reported an 11-year-old Chinese boy with a 7-year history of recurrent, migratory arthritis. Trio whole-exome sequencing identified a heterozygous PSTPIP1 c.770A>G (p.Glu257Gly) variant, classified as likely pathogenic. The father carried the same variant; he had experienced arthralgias in early childhood but became asymptomatic after age 10 without any treatment, demonstrating incomplete penetrance. This variant is extremely rare, reported in only one of 16 patients in the Eurofever registry, all of European descent, making this the first Asian case. Due to financial constraints, IL-1 inhibitors were inaccessible. Tofacitinib (3.5 mg twice daily, adjusted from adult dose based on body surface area) was initiated in February 2026. After 2 months, joint swelling and pain decreased significantly. As of July 10, 2026, no recurrence of joint swelling and pain had been observed during follow-up. However, radiography revealed irreversible structural damage (bone demineralization, joint space narrowing, osteophyte formation), and the patient still had limited mobility. Rehabilitation specialists advised against aggressive range-of-motion exercises and recommended home-based ultrasound and electrical stimulation to prevent muscle atrophy. Long-term follow-up is ongoing. PAPA syndrome should be considered in children with culture-negative, antibiotic-unresponsive recurrent arthritis, even without skin findings. Early genetic diagnosis can prevent unnecessary procedures. For patients who cannot access IL-1 inhibitors, tofacitinib may reduce inflammation, but it cannot reverse established joint damage. Given the relatively short follow-up duration, the long-term durability of response, safety, and impact of tofacitinib on disease progression remain to be determined. This report provides early, preliminary evidence of JAK inhibitor use in this population, contributing initial data to the limited Asian literature.

Borrelia burgdorferi (Bb) infection can persist in protected sites like articular joints, presenting as migratory oligoarthritis characteristic of Lyme Arthritis (LA). LA is characterized by intermittent synovitis and joint swelling, but why acute infection is relapsing-remitting and not persistent remains unknown. We hypothesize that the immune response is unique to the joint space, particularly the response of Resident Synovial Macrophages (RSMs), and may be important in understanding the clinical course of acute LA and beyond. This study aimed to investigate the polarization and functional profiles of these joint lining macrophages in response to acute Bb exposure in ex vivo human synovial tissue from patients undergoing total joint replacement.

Frailty and osteoarthritis (OA) frequently coexist in older adults, yet the extent to which they share molecular programs across tissues remains unclear. We integrated bulk transcriptomics, peripheral immune and OA meniscal single-cell atlases, inferred cell-cell communication, and an in vitro myeloid-chondrocyte conditioned-medium model. Frailty-associated vastus lateralis and OA synovium shared a 16-gene program enriched for inflammatory and migratory processes, which was refined by protein-protein interaction analysis into a 15-gene hub module (Hub-15). Donor-aware pseudobulk analysis showed coordinated Hub-15 upregulation in CD8 T, natural killer, B, and monocyte/macrophage-like cells, with the highest scores in monocyte/macrophage populations. In the meniscal atlas, donor-level analysis of 7 normal and 6 OA donors identified a 20.5 percentage point lower proportion of inflammatory/stress cells and a 17.3 percentage point higher proportion of fibrochondrocyte-like cells in OA (both false discovery rate = 0.010), whereas state-specific Hub-15 differences were not significant after correction. Exploratory communication analysis nominated directionally consistent candidate myeloid-to-structural signaling axes, although none remained significant after multiple-testing correction. Conditioned medium from cytokine-primed THP-1 cells elicited inflammatory and matrix-catabolic responses in C28/I2 cells. These findings identify a cross-tissue, leukocyte-shared, and myeloid-enriched inflammatory program that converges across independent frailty and OA cohorts, providing a hypothesis-generating framework for future mechanistic testing.

Ankylosing spondylitis (AS) is an inflammatory disease marked by aberrant new bone formation and spinal ankylosis. Transforming growth factor-β1 (TGFβ1) is implicated in osteogenesis, yet its downstream effectors in AS remain unclear. Osteonectin, a glycoprotein secreted by osteoblasts, plays a critical role in bone formation with TGFβ1, but has not been studied in AS. This study aimed to investigate the TGFβ1-osteonectin mediated regulation of osteogenic activity in AS. Serum levels of TGFβ1, osteonectin, and osteocalcin were measured in AS patients and healthy controls. Measured these serum levels were compared with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Enthesis cells isolated from AS spinal tissues were stimulated with recombinant TGFβ1 in vitro. Proliferation, matrix production, migration, and clonogenicity were evaluated. Immunohistochemical staining of spinal tissues was performed to assess osteonectin expression. AS patients showed significantly elevated serum levels of TGFβ1 and osteonectin compared to healthy controls. Osteonectin expression, but not osteocalcin, was significantly correlated with serum level of TGFβ1. TGFβ1 stimulation enhanced proliferation, collagen deposition, migratory capacity, and colony formation in enthesis cells derived from AS patients. Immunohistochemistry revealed increase of osteonectin expression in periosteal regions of AS tissues. These findings suggest that osteonectin is a TGFβ1-responsive effector involved in early osteoprogenitor activation and may contribute to pathological bone formation in AS. Osteonectin represents a potential biomarker and therapeutic target for early structural progression in AS.

Currently, utilized disease-modifying antirheumatic drugs (DMARDs) do not provide a complete cure for rheumatoid arthritis (RA) and are associated with side effects related to prolonged use. In contrast, natural products have demonstrated promising efficacy and low toxicity in treating various diseases. This study employed network pharmacology and virtual screening to identify natural products with potential therapeutic effects for RA, followed by molecular dynamics simulations and experimental validation. Through network pharmacology, we identified interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) as RA-related targets, and subsequently prioritized neoprzewaquinone A (NEO) via virtual screening and molecular dynamics simulations for further validation. Subsequent experiments indicated that NEO could inhibit the binding of IL-1β, IL-6, and TNF-α to their respective receptors, reduce proliferation, and downregulate the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS). Furthermore, NEO alleviated RA-related symptoms and diminished tissue damage in collagen-induced arthritis (CIA) mice. RNA sequencing suggested that the alleviative effect of NEO on RA may be attributed to the inhibition of the activation of the MAPK signaling pathway. Additionally, NEO appeared to reduce the phosphorylation levels of MEK and ERK. Importantly, safety evaluations did not reveal a clear increase in liver or kidney toxicity associated with NEO, within the scope of this study. Collectively, these findings suggested that NEO shows promise as a potential natural therapeutic option for RA and offers a new direction and theoretical foundation for future pharmacotherapy research in this area.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene, characterized by systemic inflammation and hematologic abnormalities. Due to its broad and overlapping clinical manifestations, VEXAS is frequently misdiagnosed as other rheumatologic or hematologic conditions, leading to delays in diagnosis. We present the case of a 67-year-old man initially diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who developed progressive multisystem inflammatory disease, including migratory inflammatory arthritis, chondritis, scleritis, constitutional symptoms, and persistent macrocytic anemia. Despite treatment with corticosteroids and rituximab, his symptoms persisted. Bone marrow biopsy demonstrated cytoplasmic vacuolization in myeloid and erythroid precursors, and subsequent next-generation sequencing identified a somatic UBA1 mutation, confirming the diagnosis of VEXAS syndrome. His clinical course was further notable for the development of neutrophilic dermatosis consistent with Sweet's syndrome. This case highlights the diagnostic complexity of VEXAS syndrome and underscores the importance of recognizing characteristic clinical patterns, including macrocytic anemia, chondritis, and dermatologic manifestations, particularly in older male patients with refractory inflammatory disease. Early consideration of VEXAS and timely molecular testing may reduce diagnostic delay and facilitate more targeted management of this emerging hematoinflammatory disorder.

Myeloid lineage-derived cells are key orchestrators of immune function and contribute to several chronic inflammatory disorders, such as rheumatoid arthritis (RA). The landscape of how these detrimental pro-inflammatory roles evolve over the course of the disease and the impact of therapies on them is being unraveled by recent immune-cell profiling studies. An alternative phenotyping using CD4 and CD45R0 expression to assess monocyte (Mo) and DC subsets allowed us to re-evaluate CD26 expression, an antigen with key migratory functions via its dipeptidyl peptidase (DPP4) activity on chemokines, in myeloid cells. Myeloid DCs barely express CD26 (while plasmacytoid pDCs do), and the intermediate Mo (intMo) subset is enriched in CD26. In a cohort of RA patients under treatment, together with the known expansion of Mo and the impairment of DC subsets and intMo, the CD26 expression was reduced, except for the intMo subset, enriched in CD26. The CD26 expression levels correlated with disease activity (DAS28 and its components), with therapy-specific patterns. Treatment with classical or biologic DMARDs, anti-IL6R, CTLA4-Ig, anti-TNF and anti-CD20, differentially modulated Mo subsets, the latter two reducing classical monocytes (cMo) while anti-TNF modestly increasing pDCs frequencies. Only anti-IL6R therapy increased total intMo % while decreasing the CD26+ intMo % (anti-CD20 also decreased the latter; on the contrary, CTLA4-Ig and anti-TNF increased it). Therapies variably restored CD26 density, except for anti-IL6R and anti-CD20. In conclusion, given that DPP4 inhibitors have shown contradictory effects in RA, their specific impact on these CD26+ APC functions warrants further investigation. Furthermore, the strong both positive and negative correlations found between soluble sCD26 levels and CD26+ frequencies (most strongly with pDCs) might support a sCD26 secretion independent of membrane-bound CD26, and CD26+ cell frequency associations with levels of anti-CD26 autoantibodies might suggest Ag-Ab complexes involvement on CD26 expression only in certain contexts.

Spatial organisation of immune cells reflects a balance between tissue anchoring and migratory compatibility, yet how this balance is structured within inflammatory skin disease remains poorly understood. Spatial transcriptomic analyses defined transit-retention immune organisation across lesional and non-lesional skin in atopic dermatitis (AD) and psoriasis (PsO). A unified transit-retention axis captured contextual immune organisation within leukocyte-rich tissue microenvironments. Non-lesional skin in both diseases exhibited retention-dominant organisation. In contrast, psoriatic lesions showed disruption of retention dominance, accompanied by coordinated alignment of antigen presentation, T cell activation, Th17, and B cell programmes with transit-compatible organisation, a pattern not observed in AD. An independent spatial transcriptomic dataset of psoriatic skin enabled assessment of compartmental specificity and clinical relevance. These analyses identified the epidermis as the primary site of transit-skewed reorganisation, with epidermal transit alignment scaling with disease severity. Extension of the same transcriptional framework to circulating adaptive immune cells using CITE-seq revealed lineage-specific transit-associated features in psoriatic disease. Circulating CD4 T cells and B cells showed stronger transcriptional and protein-level alignment with transit-associated states in PsO and psoriatic arthritis. Together, these analyses reveal transit-skewed adaptive immune organisation as a unifying feature of psoriatic disease.