The long-term outcome of lung transplantation remains inferior to that of other solid organ transplants, primarily due to rejection/infection. This pilot study investigates longitudinal changes in the bronchoalveolar lavage (BAL) leukocyte transcriptomes and phenotypes, and their impact on clinical outcomes. BAL samples were collected at baseline and 1-12 mo posttransplantation. Leukocyte phenotypes, activation status, and biomarkers were characterized alongside their gene expression profiles. We identified distinct BAL leukocyte transcriptional signatures associated with allograft rejection across 2 independent cohorts. Alveolar macrophages (AMs) predominated after transplantation, whereas granulocytes increased during the first year. This was associated with decreased expression of CD163, an anti-inflammatory marker, and increased expression of proinflammatory markers CD80 and CD86 on AMs. In a patient subgroup, a unique foamy macrophage (FM) subset with distinct cytology, featuring cytoplasmic lipid-laden vacuoles, was identified and confirmed in lung biopsies. FMs were accompanied by a unique non-FM (no-FM) population and were associated with elevated BAL levels of interleukin (IL)-8, IL-1β, and IL-10 and more frequent hospital readmissions. BAL transcriptomic analysis for patients carrying both FMs and no-FMs showed upregulation of genes linked to lipid metabolism, leukocyte chemotaxis, and inflammatory response pathways. We identified a rejection gene signature and proinflammatory shift in BAL leukocyte phenotypes after lung transplantation. The presence of FMs/no-FMs was associated with proinflammatory changes and worse clinical outcomes as per our data analysis, unadjusted for confounders due to relatively limited sample size. These findings could facilitate further investigations into early detection of lung allograft rejection and help focus on AM-targeted interventions.

Myelin debris uptake by macrophages and microglia: Resolution of foam cells with a series of novel cyclodextrins

Hypercholesterolemia and a high-fat diet promote 2 macrophage subtypes involved in atherosclerosis by inducing lipid droplet accumulation in foamy macrophages (FMs) and triggering inflammatory activation in non-foamy macrophages (NFMs). MicroRNAs are key regulators of macrophage subtypes in atherosclerosis; for instance, miR-10a-5p limits lipid droplet formation, while miR-155-5p enhances inflammation. miR-147-3p is upregulated by inflammatory stimuli in macrophages and in atherosclerotic lesions, suggesting a potential role in NFMs. The role of miR-147-3p in macrophages, with or without enhanced green fluorescent protein expression, in atherosclerosis was examined in Apoe-/- (apolipoprotein E-deficient) mice with a myeloid cell-specific knockout of the microRNA 147 (Mir147) gene. Using live-plaque 4D confocal imaging, we assessed lipid droplets, caspase-3 activation, phagocytosis of apoptotic DNA, cholesterol crystal (CC) formation, mitochondrial function, macrophage migration, and tubular membrane extension formation. Green fluorescent protein-tAgo2 (tagged Argonaute 2) immunoprecipitation combined with prime RNA sequencing was performed using atherosclerotic aortas from Apoe-/- mice that expressed tAgo2 in myeloid cells. The effect of the galectin-3 inhibitor GB1107 was studied using 4D live-plaque imaging. Unlike FMs, NFMs are primarily located in the plaque core and show higher miR-147-3p levels in both mouse and human atherosclerosis. Knocking out Mir147 in myeloid cells increases atherosclerosis, with enhanced CC formation and apoptotic DNA accumulation in necrotic cores. Removing Mir147 reduces mitochondrial activity and elevates caspase-3 activity in NFMs, but not in FMs, and lowers the spare respiratory capacity of plaque macrophages. Moreover, deleting Mir147 impairs NFM uptake of apoptotic DNA, increases extracellular apoptotic DNA, and promotes CC formation. Additionally, Mir147 deficiency in NFMs induces caspase-3 activation in endothelial cells, facilitating the transendothelial extension of FM projections. The Lgals3 transcript, encoding galectin-3, was reduced in the tAgo2 immunoprecipitate after Mir147 knockout. A miR-147-3p binding site in the Lgals3 3'-UTR was functionally confirmed. GB1107 treatment reversed the Mir147 knockout effect in macrophages. miR-147-3p reduces atherosclerosis by suppressing the harmful effects of NFMs on endothelial cells and by enhancing their clearance of apoptotic DNA through targeting galectin-3. Increasing miR-147-3p levels might thus slow the expansion of the necrotic core and reduce atherothrombosis caused by NFM-induced endothelial damage.

Immune-Related Pathological Features and Predictive Score in Intrahepatic Cholangiocarcinoma Treated With Combined Conversion Immunotherapy.

Pulmonary alveolar proteinosis (PAP) is a rare lung disease with primary (usually autoimmune) and secondary forms. Unlike the autoimmune type, which can be treated with cytokine therapy or whole-lung lavage, the secondary form associated with occupational particulate exposure, such as indium compounds, has no established therapy and remains challenging to treat. PAP was experimentally induced in rats through intratracheal exposure to indium oxide nanoparticles (In2O3 NPs). To assess potential therapeutic interventions, we administered four pharmacological agents: aspirin and naproxen, which are expected to attenuate inflammation, and pioglitazone and indomethacin, peroxisome proliferator-activated receptor (PPAR)-γ agonists anticipated to restore impaired surfactant homeostasis. The efficacy of their amelioration of In2O3 NP-induced PAP and the underlying mechanisms were evaluated by bronchoalveolar lavage fluid analysis, histopathology, and gene expression profiling. Treatment with pioglitazone and indomethacin markedly attenuated In2O3 NP-induced PAP by reducing foamy macrophage accumulation and restoring the expression of PPAR-γ and its downstream ATP-binding cassette (ABC) transporters, such as ABCG1 and ABCG4. In contrast, aspirin and naproxen only slightly decreased neutrophil infiltration. Among the tested agents, indomethacin showed relatively pronounced effects on several PAP-related endpoints, suggesting its potential to improve macrophage lipid handling and surfactant balance. Targeting PPAR-γ-dependent macrophage lipid regulation may serve to attenuate In2O3 NP-induced secondary PAP-like pathology by reducing foamy macrophage accumulation and improving surfactant clearance. The effects were more pronounced when treatment was administered before disease establishment, whereas established pathology was only partially reversed, supporting the PPAR-γ-ABC transporter pathway as a potential target for future intervention.

The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflammation, with links to increased susceptibility to cardiometabolic diseases. This study investigates the role of ARF in lung homeostasis and reveals that its deficiency in mice affects lipid metabolism and leads to pulmonary abnormalities resembling pulmonary alveolar proteinosis (PAP). ARF-deficient mice exhibited abnormal surfactant clearance, characterized by lipid and protein accumulation in the alveoli, foamy alveolar macrophages (AMs) with enlarged and vacuolated morphology, and increased bronchoalveolar lavage fluid turbidity. These changes were linked to disrupted surfactant homeostasis resulting from an imbalance between increased lipid uptake (via upregulation of scavenger receptors such as SR-A1 and CD36) and impaired lipid efflux, evidenced by reduced expression of the cholesterol transporter SR-BI. These mice also display reduced AM numbers, increased eosinophil and neutrophil infiltration, consistent with secondary PAP. Additionally, a distinctive chemokine and cytokine profile (elevated Ccl12, Ccl2, Cxcl1, and IL-10) was observed, which may be associated with type 2 immune responses and alternative AM polarization. Interestingly, ARF deficiency also appears to compromise AM maintenance through effects on self-renewal and survival. Pulmonary function tests revealed increased tissue elastance and damping, suggesting early-stage lung stiffness. Collectively, these findings highlight the essential role of ARF in lung homeostasis and lipid regulation, providing insights into its potential involvement in PAP pathogenesis.

ABSTRACTBackgroundBenign prostatic hyperplasia (BPH) encompasses a heterogeneous set of pathological processes that instigate lower urinary tract symptoms (LUTS). Using a mouse model of steroid hormone imbalance–induced lower urinary tract dysfunction, we identified luminal lipid‐laden foamy macrophages, although their presence and contribution to human pathology have not yet been established. The objective of this study was to determine whether luminal macrophages are associated with human BPH and to assess how lipid accumulation relates to underlying pathological features and clinical parameters.MethodsWhole‐mount tissue sections from simple prostatectomy specimens and prostates from healthy donors were used to evaluate the association of luminal macrophages by immunohistochemistry and lipid content by Oil Red O staining. For a systematic assessment of inflammatory cells (CD45⁺ and CD68⁺), collagen content (Picrosirius Red), glandular proportion (H&E), and lipid accumulation, prostate tissues were obtained from patients undergoing holmium laser enucleation of the prostate (HoLEP). Clinical data, including IPSS and LURN symptom scores, were collected, and relevant clinical variables were extracted by chart review. Pathological subtypes were subsequently identified using unsupervised hierarchical clustering.ResultsLumens containing CD68⁺ macrophages were increased 6.2‐fold and 6.6‐fold in glandular nodules and internodular regions, respectively, compared with the transition zone of donors. Overall lipid content was also elevated by 2.8‐fold in glandular nodules relative to healthy transition zone tissue. In HoLEP specimens, lipid content showed positive correlations with glandular proportion, CD45⁺ and CD68⁺ cell abundance, prostate volume, and serum PSA, and negative correlations with collagen content and body mass index. Unsupervised hierarchical clustering of pathological features identified four distinct subtypes: a small, stromal‐fibrotic phenotype; a glandular‐enriched, low‐immune phenotype; a large‐prostate subtype characterized by high lipid content and inflammation; and a macrophage‐enriched phenotype. Notably, the small stromal‐fibrotic subtype was enriched for patients receiving 5α‐reductase inhibitor therapy.ConclusionsIn summary, our findings identify luminal macrophages and lipid accumulation as previously underrecognized pathological features of BPH. Lipid accumulation is associated with prostatic inflammation and may represent a therapeutic target. Luminal macrophages may further contribute to disease progression, and comprehensive transcriptomic and proteomic characterization of these cells in human tissue will be essential to elucidate their pathological functions. Importantly, effective implementation of subtype‐informed BPH management will require improved biomarkers and imaging strategies to enable accurate disease stratification and personalized treatment selection.

A 27-year-old male presented with a one-month history of multiple asymptomatic yellow papules on the extensor surfaces of the elbows, occipital scalp and back. Dermoscopic examination showed yellow clods, arborising vessels and an erythematous-brown halo. Histopathologic examination revealed foamy macrophages in the dermis. Lipid profile and haemoglobin A1c levels were elevated. The patient was diagnosed with eruptive xanthoma in the setting of hypertriglyceridaemia and poorly controlled diabetes.

Invasive micropapillary carcinoma (IMPC) is a rare subtype of breast cancer, characterized by infiltrative growth and morula-like cell aggregates without fibrovascular cores. We recently encountered an unusual invasive breast carcinoma with a thick fibrous capsule resembling encapsulated papillary carcinoma but with micropapillary features. A 71-year-old woman presented with a palpable mass in the left breast. MRI revealed a 10 cm enhancing oval mass. Core needle biopsy was performed to diagnose invasive carcinoma with micropapillary features [estrogen receptor (ER) and progesterone receptor (PR)-positive, HER2-negative]. The patient received neoadjuvant chemotherapy, followed by a mastectomy with sentinel lymph node biopsy. The mastectomy revealed a well-circumscribed 11 cm mass surrounded by a fibrous capsule. The tumor consisted of tubulo-micropapillary structures without fibrovascular cores, lined by a single layer of cuboidal cells containing nests of foamy macrophages. Rare foci of lymphovascular invasion were observed. Two sentinel lymph nodes were negative. To our knowledge, invasive micropapillary carcinoma with an encapsulated pattern has not been previously reported.

Oncocytic Papillary Renal Cell Carcinoma (OPRCC) is a rare variant of Papillary Renal Cell Carcinoma (PRCC), characterised by distinct morphological and immunophenotypic features. Present report is of a 75-year-old hypertensive female who presented with constipation and abdominal bloating for four months. Imaging revealed an exophytic lesion in the lower pole of the right kidney, measuring 6.1×5.8×5.4 cm, without perinephric or sinus invasion. Laboratory studies demonstrated mild haematuria, elevated Lactate Dehydrogenase (LDH), and hypercalcaemia. The patient subsequently underwent radical nephrectomy. Gross examination revealed a 6.5 cm brown-yellow tumour with haemorrhagic areas, confined to the kidney. Histopathology showed papillary structures lined predominantly by oncocytic cells with abundant granular eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Focal pseudostratification, nuclear atypia, haemosiderin deposition, foamy macrophages, and focal necrosis were present, with no capsular, vascular, or nodal involvement. Immunohistochemistry (IHC) demonstrated diffuse positivity for Alpha-MethylacylCoA Racemase (AMACR), vimentin, and CD10, with negativity for CK7, CD117, and Ki-67, confirming the diagnosis of OPRCC. Postoperative recovery was uneventful, and a structured surveillance plan was initiated. Recognition of OPRCC is crucial to prevent misdiagnosis with benign oncocytoma or more aggressive RCC subtypes, enabling appropriate prognostication and management.

Early-life exposure to polyhexamethyleneguanindine phosphate resulted in persistent inflammation and alterations of lung structure later in life

Whipple’s disease is a rare, chronic systemic infection caused by Tropheryma whipplei that commonly presents with gastrointestinal manifestations but may involve multiple extraintestinal organs. Cardiac involvement, particularly culture-negative endocarditis, is described; however, pulmonary complications such as pulmonary hypertension (PH) are uncommon. We report a case of Whipple’s disease presenting with severe pre-capillary pulmonary hypertension and right ventricular (RV) failure with reversibility following antimicrobial therapy. A 62-year-old woman with seropositive rheumatoid arthritis on adalimumab, presented with one month of profuse watery diarrhoea, abdominal pain, dizziness and weakness. Imaging revealed diffuse mesenteric and para-aortic lymphadenopathy. Upper endoscopy demonstrated oedematous whitish granular villi in the duodenum, and biopsies showed periodic acid–Schiff–positive, acid-fast bacillus–negative foamy macrophages diagnostic of Whipple’s disease. Transthoracic echocardiography revealed RV dilation and dysfunction with pulmonary hypertension, which was confirmed on right heart catheterisation as severe pre-capillary PH with elevated pulmonary vascular resistance and normal wedge pressure. The patient developed RV-predominant cardiogenic shock requiring inotropic and vasopressor support. Following initiation of intravenous ceftriaxone her haemodynamics improved rapidly, with normalisation of cardiac output and marked reduction in pulmonary pressures on repeat catheterisation. Gastrointestinal symptoms resolved, immunosuppressive therapy was discontinued, and she was discharged on prolonged antimicrobial therapy. This case underscores PH as a rare but potentially reversible manifestation of Whipple’s disease. Recognition of this entity is critical, as PH-specific vasodilator therapy alone is often ineffective, whereas early targeted antimicrobial treatment can result in rapid and profound clinical and haemodynamic recovery, even in cases presenting with severe RV failure.LEARNING POINTSWhipple’s disease should be considered in the differential diagnosis of otherwise unexplained pre-capillary pulmonary hypertension, particularly when accompanied by chronic diarrhoea, arthralgia or systemic features.Unlike idiopathic pulmonary arterial hypertension, Whipple’s disease-associated pulmonary hypertension is often driven by a reversible inflammatory process and may present with severe right ventricular failure and haemodynamic compromise.Recognition of this rare entity is critical, as pulmonary hypertension-specific vasodilator therapy alone is frequently insufficient, whereas timely initiation of targeted antimicrobial treatment can result in rapid and profound clinical and haemodynamic recovery.

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently recognized renal tumor characterized by papillary architecture lined by a single layer of low-grade eosinophilic cells with apically located nuclei. In the latest WHO classification, they are not recognized as a distinct entity but rather as a morphological pattern of papillary renal cell carcinoma. To date, limited studies have compared PRNRP with eosinophilic/oncocytic papillary renal cell carcinoma (E/OPRCC), which they are not infrequently confused with, although a few previous comparisons with classic papillary renal cell carcinoma have already identified several distinguishing features. A comparative analysis of 15 of PRNRPs and 16 of E/OPRCC cases was conducted, evaluating their histopathological, immunophenotypic, interphase cytogenetic, and molecular profiles. PRNRPs demonstrated distinctive morphological features, including consistent apical nuclear positioning, absence of foamy macrophages in the papillary cores (p = 0.0001), and a lower nucleolar grade compared to E/OPRCCs (p = < 0.0001). Immunohistochemically, PRNRPs exhibited strong and uniform GATA3 expression and were negative for vimentin, CD10, and CD13, in contrast to E/OPRCCs. Cytogenetically, PRNRPs lacked trisomies of chromosomes 7 and 17, which were present in ~ 40% of E/OPRCCs (p = 0.0262). Notably, all PRNRP cases harbored KRAS mutations, absent in E/OPRCCs (p < 0.0001). Our findings support the classification of PRNRP as a distinct renal tumor entity, separated from both classic papillary renal cell carcinoma and its eosinophilic/oncocytic morphological variant.

Vasculitis that clinically and pathologically affects the central nervous system (CNS) alone is defined as primary or isolated CNS vasculitis. Although rare, it is a diagnosis that should be considered by internists and neurologists in patients presenting with progressive neurological signs and symptoms of uncertain origin. There is no specific imaging or laboratory pattern that guides the diagnosis, and aside from biopsy, magnetic resonance imaging (MRI) is the only study that can substantially contribute to a definitive diagnosis. We report the case of a 20 -year -old man from Campeche diagnosed with small -vessel CNS vasculitis who initially presented with cognitive impairment. Polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) was positive for Epstein -Barr virus. Two brain biopsies were performed, both revealing lymphocytic vasculitis with perivascular necrosis and foamy macrophages associated with secondary demyelination, Chronic vascular injury may manifest as cognitive decline; however, its occurrence as an initial presentation is extremely rare. This case represents a clear example of the diagnostic challenge posed by vasculitis, particularly when neurological manifestations are the sole clinical findings, and underscores the importance of biopsy in the diagnostic approach.

Background. Acid sphingomyelinase deficiency (Niemann – Pick disease) leads to the intracellular accumulation of sphingomyelin within the mononuclear phagocyte system, including liver, spleen, lungs and bone marrow. Liver involvement represents one of the earliest and persistent visceral manifestations of the disease. Foamy macrophages featuring prominent cytoplasmic vacuolation are generated within the liver. Intracellular accumulation of pathological substrates in hepatocytes results in several pathological changes, including inflammation and cytokine release, remodeling of the sinusoidal network, periportal and bridging fibrosis and progressive portal hypertension. Dyslipidemia, associated with Niemann – Pick disease, is characterised by elevated levels of various lipid fractions. Gradual lipid accumulation leads to the liver enlargement (hepatomegaly) and the development of hepatic steatosis. Hepatomegaly, biochemical abnormalities and progressive fibrosis significantly impair the patients' quality of life and adversely affect the prognosis of the disease. Objective. To analyze current data on the pathogenesis, clinical manifestations, morphological features, and treatment of liver damage in Niemann – Pick disease types A, A/B, and B. Materials and methods. A systematic review of publications from 2013-2025 on the clinical presentation, histopathology, and treatment of acid sphingomyelinase deficiency was conducted, including the impact of enzyme replacement therapy on liver pathology. Results. The liver is a key target organ in Niemann – Pick disease types A, A/B, and B. The spectrum of liver changes includes hepatomegaly, parenchymal infiltration with foamy macrophages, progressive fibrosis, cirrhosis, hepatic steatosis, and the possible development of portal hypertension and liver failure requiring transplantation. The severity of liver damage and the age at onset of changes depend on the disease phenotype. Liver failure, in addition to respiratory disease, is the leading cause of death in chronic forms of Niemann – Pick disease. Modern enzyme replacement therapy can reduce liver volume, improve biochemical parameters, and slow the progression of fibrosis. Conclusion. Early diagnosis and pathogenetic therapy are key to slowing the progression of liver disease in acid sphingomyelinase deficiency.

Polymorphisms of mouse chitinase-like protein 3 (Chil3), a member of the mammalian chitinase-like protein (CLP) family, have been demonstrated to be associated with inflammatory diseases by regulating lipid metabolism. However, the specific immunomodulatory impacts of CLPs, mainly mouse CHIL3 and its human functional homologue chitinase-3-like 2 (CHI3L2), on macrophage cholesterol metabolism and atherosclerosis have remained unclear. Here, we find CLPs (CHIL3 and CHI3L2) accelerate atherogenesis in a macrophage-dependent manner. Mechanistically, we identify an autocrine mechanism through which CLPs regulate cholesterol metabolism in macrophages. Macrophage-secreted CLPs exacerbate lipid uptake by binding to CD36. CLPs exhibit glycosidase activity, targeting and hydrolyzing N-glycosylated glycans on CD36, predominantly at sites N220 and N321, thereby enhancing lipid uptake. Increased lipid influx activates mTOR in macrophages, driving their transition to a pro-inflammatory phenotype while simultaneously suppressing peroxisome proliferator-activated receptor gamma (PPARγ) expression and thus impairing ABCG1-mediated cholesterol efflux. Single-cell sequencing reveals that CLPs increase atherosclerotic foamy macrophages, favoring vascular smooth muscle cells (VSMC) transformation into foam and osteoblast-like cells. Additionally, neutralizing antibodies targeting CHI3L2 prevent and treat atherosclerosis. These findings highlight the potential of CLPs as targets for disease diagnosis and therapy.

Oral verruciform xanthoma (OVX) is a rare benign lesion of the oral mucosa that often mimics other oral diseases. We report three cases of OVX and describe their clinical and histopathological characteristics. All patients presented with asymptomatic, well-demarcated verrucous lesions located on the attached gingiva. The patients ranged in age from 59 to 85 years, with a median age of 73 years. One patient had a history of umbilical cord blood transplantation and possible chronic graft-versus-host disease. Clinically, the lesions were suspected to represent papillary lesions. Excisional biopsy was performed in all cases. Histopathological examination demonstrated papillary epithelial architecture with elongated rete ridges and infiltration of foamy macrophages within the underlying connective tissue, thereby confirming the diagnosis of OVX. No recurrence was observed during the follow-up period. These findings emphasize the importance of histopathological evaluation for the accurate diagnosis of OVX.

ABSTRACT Amiodarone hydrochloride is an effective antiarrhythmic drug that can cause serious adverse effects, including amiodarone‐induced pulmonary toxicity (APT). We report a case of an 81‐year‐old man who presented with cough, sputum and progressive dyspnoea 10 months after receiving amiodarone therapy following electrical cardioversion for atrial fibrillation. Chest computed tomography (CT) revealed diffuse bilateral ground‐glass opacities. Bronchoalveolar lavage fluid demonstrated lymphocytosis with foamy macrophages, whereas infectious aetiologies were excluded. Although the cumulative amiodarone dose was relatively low (approximately 60 g), the serum mono‐desethyl‐amiodarone concentration was 0.75 μg/mL. APT was diagnosed based on the clinical, radiological and bronchoalveolar lavage findings. The patient's condition showed rapid clinical and radiological improvements after amiodarone was discontinued and corticosteroid therapy was initiated. Elevated serum concentrations of mono‐desethyl‐amiodarone are associated with an increased risk of APT. This case suggests that measuring mono‐desethyl‐amiodarone levels may facilitate APT diagnosis, even at lower cumulative doses of amiodarone.

Obesity is a major stroke risk factor. By 72 h after ischemia, obese mice exhibit greater stroke sizes, neuroinflammation, and motor deficits. However, the immune mechanisms driving these outcomes remain incompletely understood. To define how obesity reshapes the immune response to stroke, we performed single-cell RNA sequencing of immune cells in the blood and brain 72 h after stroke or sham surgery in control-diet and diet-induced obese mice. In the blood, macrophages and neutrophils from obese mice exhibited the most pronounced transcriptional changes under both sham and stroke conditions. These changes included Ly6c2-Cd68-Cx3cr1-enriched monocyte-derived transitioning macrophages and classic macrophage populations enriched in the lipid droplet gene perilipin-2 (Plin2) with one also enriched with foamy macrophage marker Cd36; chemotaxis-associated neutrophil subtypes enriched in Cxcl2 or Cxcr2; and interferon-signaling neutrophils. Obese mice after sham surgery exhibited minimal immune changes in the brain, but after stroke, we report substantial transcriptional changes in infiltrating monocyte-derived macrophages with high or intermediate Plin2 expression, interferon-signaling dendritic cells, and Cxcl2-enriched neutrophils. The obesity-induced changes in immune cells across both blood and brain are characterized by elevated lipid handling, inflammation, cellular stress, and notable coagulation pathways in the brain neutrophils. Co-expression analyses revealed that elevated Plin2, a hallmark of obesity, is positively correlated with lipid-related, immune, stress, and pro-thrombotic genes. We tested its role by stereotactically injecting Plin2 siRNA into the stroke. In non-obese mice, Plin2 knockdown increased infarct size and worsened motor outcomes despite reducing inflammatory markers (CD68, IFITM3, and TSPO), suggesting that early lipid droplet accumulation is neuroprotective and stimulates the immune response to stroke. In obese mice, Plin2 knockdown mildly worsened motor deficits while reducing obesity-elevated CD68. Collectively, these findings identify elevated lipid handling, neuroinflammation, cellular stress, and coagulation as key transcriptional features of obesity-exacerbated stroke outcomes while revealing a protective role for Plin2.

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-κB-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.