Lipid-laden Foamy Macrophages Research Articles

Xanthogranulomatous mastitis: a rare entity presenting with breast lump and mimicking fibroadenoma in a young female

Introduction and importance: Xanthogranulomatous mastitis is a rare chronic granulomatous inflammation of breast tissue, characterized by the presence of multinucleated giant cells, lipid-laden foamy macrophages, and cholesterol crystals. The breast is an extremely rare location for xanthogranulomatous inflammation. Case presentation: The authors describe a case of xanthogranulomatous mastitis in a 26-year-old female patient who presented with a 4×5 cm lump in her right breast. After ultrasonography (revealed a well-circumscribed hypoechoic lesion, with increased vascularity), and surgical consultation, an excisional biopsy was done, and sent for histopathologic examination, which showed features suggestive of xanthogranulomatous mastitis. Clinical discussion: Xanthogranulomatous mastitis, clinically as well as radiologically mimics some other conditions of breast like breast cancer, or fibroadenoma. Ultrasonography usually reveals a well-circumscribed hypoechoic lesion, with increased vascularity, and mammography usually shows BIRADs 3 to 5. Diagnosis is usually based on histopathologic findings of multinucleated giant cells, lipid-laden foamy macrophages, and cholesterol crystals. Treatment is usually surgical excision. Conclusion: Though xanthogranulomatous inflammations are rare in the breast, they must be considered a differential diagnosis in patients presenting with various breast symptoms like lump, pain, or features of breast malignancy.

PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site

After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of the foamy macrophage phenotype in vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and inhibition of this pathway decreased their lipid content, inflammatory cytokines, and ROS production. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy and decreased phagocytosis after PI3K inhibition as potential mechanisms for reduced lipid accumulation. Together, our data suggest that the formation of pro-inflammatory foamy macrophages after SCI is due to the activation of PI3K signaling, which increases phagocytosis and decreases autophagy.

The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.

A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.

Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.

Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease.

Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature

BackgroundErdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported.Case presentationA 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions.ConclusionsECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries.

The tuberculosis resistance protein TOLLIP prevents disease progression by regulating the integrated stress response in alveolar macrophages.

Abstract Genetic variation associated with decreased TOLLIP expression in macrophages is a tuberculosis (TB) risk factor. However, the fundamental mechanisms underlying TOLLIP’s role in TB pathogenesis and macrophage function are unknown. To understand why TOLLIP strongly influences Mtb-macrophage interactions, we infected B6 mice lacking Tollip (Tollip−/−) with Mtb and evaluated lung-resident macrophage function and clinical response. Tollip−/− mice developed worsened Mtb disease with profuse lipid-laden foamy macrophages in their lungs. This phenotype was intrinsic to AM, as Tollip−/− AM, but not other lung-resident macrophage subtypes, from mixed bone marrow chimeras selectively harbored excessive Mtb bacilli and intracellular lipid. Global gene expression analysis of Mtb-infected, Tollip−/− AM demonstrated alteration in dozens of genes consistent with the integrated stress response (ISR), which adapts cells to variable environmental conditions and is associated with TB progression. Administration of mycolic acid, an Mtb cell wall lipid, to Tollip−/− macrophages induced lipid accumulation, ISR, and increased intracellular Mtb burden. Pharmacologic ISR inhibition restored host defense in Tollip−/− mice and improved Mtb outcomes overall. In humans, TOLLIP mRNA expression was increased in caseous TB granulomas, providing translational relevance for our observations. Taken together, TOLLIP deficiency in AMs induces foam cell formation and ISR after Mtb infection, which permits increased replication and drives immunopathology. These findings illustrate a major mechanism by which TOLLIP-deficient individuals are susceptible to TB disease and suggest novel targets for TB host-directed therapy.

Xanthogranulomatous cholangitis mimicking cholangiocarcinoma: Case report and review of literature.

IntroductionXanthogranulomatous cholangitis is an extremely rare diagnosis and is believed to be an extension of xanthogranulomatous cholecystitis, a benign inflammatory process characterized by lipid-laden foamy macrophages (called “xanthoma cells”) occurring in a background of chronic inflammation consisting of lymphocytes, plasma cells, and eosinophils. Here, we report a case of xanthogranulomatous cholangitis mimicking cholangiocarcinoma.Case presentationA 72 year old male with history of recurrent cholangitis had preoperative workup highly suggestive of intrahepatic cholangiocarcinoma. He underwent right hepatectomy and portal lymphadenectomy, with pathology showing xanthogranulomatous cholangitis, with no evidence of malignancy. Interestingly, the patient did not have xanthogranulomatous cholecystitis.DiscussionWe reviewed the current literature on xanthogranulomatous cholangitis, and identified only 14 previously reported cases. In our case series, there were six female and eight male patients. Among the 14 patients, 11 presented to the hospital with jaundice. Twelve patients had preoperative workup concerning for malignancy. The diagnosis of xanthogranulomatous cholangitis was confirmed through pathology in 13 patients, and through endoscopic ultrasound biopsy in one patient. In our review, seven patients had associated xanthogranulomatous cholecystitis, three patients had an isolated case of xanthogranulomatous cholangitis, and four patients had unknown status. Our patient is the fourth case of isolated xanthogranulomatous cholangitis without xanthogranulomatous cholecystitis.ConclusionXanthogranulomatous cholangitis is a very rare phenomenon that can lead to benign strictures of the bile ducts, especially in the setting of recurrent cholangitis. It can mimic malignancies, such as cholangiocarcinoma, and should be considered in the differential diagnosis.

Excess iron promotes emergence of foamy macrophages that overexpress ferritin in the lungs of silicosis patients.

Background and objectiveInhalation of high concentrations of respirable crystalline silica (RCS) can lead to silicosis. RCS contains varying levels of iron, which can cause oxidative stress and stimulate ferritin production. This study evaluated iron‐related and inflammatory markers in control and silicosis patients.MethodsA cohort of stone benchtop industry workers (n = 18) were radiologically classified by disease severity into simple or complicated silicosis. Peripheral blood and bronchoalveolar lavage (BAL) were collected to measure iron, ferritin, C‐reactive protein, serum amyloid A and serum silicon levels. Ferritin subunit expression in BAL and transbronchial biopsies was analysed by reverse transcription quantitative PCR. Lipid accumulation in BAL macrophages was assessed by Oil Red O staining.ResultsSerum iron levels were significantly elevated in patients with silicosis, with a strong positive association with serum ferritin levels. In contrast, markers of systemic inflammation were not increased in silicosis patients. Serum silicon levels were significantly elevated in complicated disease. BAL macrophages from silicosis patients were morphologically consistent with lipid‐laden foamy macrophages. Ferritin light chain (FTL) mRNA expression in BAL macrophages was also significantly elevated in simple silicosis patients and correlated with systemic ferritin.ConclusionOur findings suggest that elevated iron levels during the early phases of silicosis increase FTL expression in BAL macrophages, which drives elevated BAL and serum ferritin levels. Excess iron and ferritin were also associated with the emergence of a foamy BAL macrophage phenotype. Ferritin may represent an early disease marker for silicosis, where increased levels are independent of inflammation and may contribute to fibrotic lung remodelling.

Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and exvivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. Invitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice.

ACUTE AMIODARONE TOXICITY PRESENTING AS A LUNG MASS

TOPIC: Imaging TYPE: Medical Student/Resident Case Reports INTRODUCTION: We present a very uncommon case of lung mass developed within a month of starting amiodarone in an elderly male. CASE PRESENTATION: An 82-year-old male with a past medical history of end-stage renal disease on hemodialysis, congestive heart failure, diabetes mellitus, coronary artery disease, atrial fibrillation on amiodarone (200mg/day started a month ago) presented with dry cough and altered mental status for one day. On exam, he appeared tachypneic and drowsy with mild bibasilar lungs crackles. Laboratory findings included WBCs 4.8 K/UL, procalcitonin 0.3 ng/ML with sterile blood, urine, and respiratory cultures. Chest x-ray showed a new right upper lobe opacity with persistent bilateral lower lobes congestion (figure 1a). Computerized tomography (CT) of the chest showed dense, irregular soft tissue mass with high attenuation at the right apex and adjacent smaller spiculated nodules compatible with the deposition of amiodarone (figure 1b). Pulmonary and cardiology services advised stopping amiodarone with no further intervention. Bronchoscopy and biopsy were not done due to poor cardiac function. He was discharged to a nursing home after a significant improvement in his symptoms. On follow up after a year, patient had complete resolution of the symptoms. DISCUSSION: Amiodarone is a widely used iodinated antiarrhythmic agent with significant side effects due to its deposition in various organs including lungs (4-17%). Organ toxicity may occur from direct cytotoxicity or T-cell mediated hypersensitivity reaction. Though there is no safe dose, amiodarone associated pulmonary toxicity is mostly suspected in patients taking a daily dose of 400 mg for more than 2 months or any dose for more than 2 years [1,2]. Life-threatening and irreversible pulmonary toxicity is frequently associated with older age, longer duration of treatment, high dosage, and pre-existing lung disease. Diagnosis is made after the exclusion of other causes in patients presenting with nonproductive cough and/or dyspnea, new chest imaging findings, biopsy showing lipid-laden foamy macrophages. Once identified, significant improvement is noted with the withdrawal of the drug. Several patterns of lung inflammation including interstitial or organizing pneumonia, pleural effusion, nodule, or mass-like lesions are evident [3]. High density (> 80 Hounsfield units) lung nodules due to iodinated-amiodarone accumulation are appreciated more on high-resolution chest CT with typical findings frequently in the upper lobes as seen in our case [3]. The mainstay of treatment includes discontinuation of the drug with or without oral steroids. Patient education, regular follow up with chest imaging and use of lowest effective doses are key in reducing its adverse effects [3]. CONCLUSIONS: Given the condition is reversible and curable; the author wants to highlight the importance of early diagnosis of the case for a favorable prognosis. REFERENCE #1: Jessurun GA, Crijns HJ. Amiodarone pulmonary toxicity. BMJ. 1997;314(7081):619-620. doi:10.1136/bmj.314.7081.619 REFERENCE #2: Schwaiblmair, M., Berghaus, T., Haeckel, T. et al. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect?. Clin Res Cardiol 99, 693–700 (2010). https://doi.org/10.1007/s00392-010-0181-3 REFERENCE #3: Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413. doi:10.1503/cmaj.061102 DISCLOSURES: No relevant relationships by Kabu Chawla, source=Web Response No relevant relationships by Resha Khanal, source=Web Response No relevant relationships by Sharad Oli, source=Web Response No relevant relationships by Shital Oli, source=Web Response No relevant relationships by Shaurya Sharma, source=Web Response

Xanthogranulomatous Breast Mass: An Unusual Presentation

Xanthogranulomatous inflammatory reactions are benign inflammatory processes characterized by aggregating lipid-laden foamy macrophages. Although cases have been reported in different organ systems, these rare reactions predominantly occur in the kidney and gallbladder. We present a 92-year-old female who noticed a palpable, tender mass in the lower inner quadrant of her right breast with no skin changes. She was referred to surgery by her primary care physician on suspicion of malignancy and further evaluation. Ultrasound-guided biopsy, ordered by the primary care provider, revealed a suspicious high-grade malignant neoplasm of uncertain origin. Pathological findings include the presence of an unusual population of malignant epithelioid cells with a striking xanthogranulomatous reaction, along with numerous Touton-like histiocytes. These findings are comparable in morphology to a recently reported xanthogranulomatous epithelial tumor. Given the lack of history of breast carcinoma in this patient as well as the lack of immunohistochemical studies suggesting breast carcinoma, treatment involved continuing standard of care for an unusual high-grade sarcoma via lumpectomy. A positron emission tomography (PET) scan was ordered to ensure there was no spread or alternate origins of the cancer tissue. This case report brings to light the findings of a probable xanthogranulomatous tumor in breast tissue, an exceptionally rare phenomenon in breast cancer, especially in the elderly population. Due to the rarity of xanthogranulomatous tumors in the breast, prognosis and standardized treatment have yet to be established.

Vasculature-on-chip for Assessment of Bioresorbable Scaffolds and Endothelial Barrier Integrity.

Endothelial cells adhere to one another through junctional structures formed by intercellular adhesion molecules. These intercellular proteins regulate barrier function in response to the hemodynamic shear rate and enable the selective passage of solutes and fluids across the endothelium. After endovascular device implantation, the endothelial barrier is compromised and becomes discontinuous, which increases permeability, allowing transmigration of leukocytes and lipoproteins and leading to the accumulation of lipid-laden foamy macrophages in the subendothelial space. Drug-coated bioresorbable vascular scaffold implants have been associated with unexpected thrombotic complications, which were not predicted in animals because of dissimilarities in endothelial regeneration and realignment between animals and humans. The development of a microengineered, microfluidics-based system of patterned channels lined with human endothelial and smooth muscle cells perfused with blood allows for the evaluation of endothelial function and barrier integrity. This review highlights the translational potential of vasculature-on-chip, which recreates the microphysiological milieu to evaluate the impact of drug-eluting bioresorbable vascular scaffolds on endothelial barrier integrity and to characterize polymer biodegradation behavior and drug release kinetic profiles over time.

Renal oncocytoma with prominent xanthomatous reaction. A rare histopathological variant of oncocytoma.

Renal oncocytoma (RO) is a distinctive neoplasm with a well-recognized gross and cytoarchitectural appearance. However, on some occasions, it may show uncommon, atypical, or worrisome gross and microscopic features potentially generating diagnostic difficulties. We herein review the oncocytoma variant characterized by a significant intraneoplastic xanthomatous reaction that produces a variegated macroscopic appearance. This feature may pose a genuine diagnostic problem with conventional (clear cell) renal cell carcinoma (RCC) because this reaction creates a departure from the typical uniform, tan-brown appearance of oncocytoma. The microscopic presence of foamy macrophages in RO may potentially lead to diagnostic difficulties with tumors exhibiting eosinophilic cells and significant infiltration for lipid-laden foamy macrophages such as cystic RCC, unclassified RCC rich in foamy macrophages, the solid variant of papillary RCC with oncocytic features, post-neuroblastoma RCC, succinate dehydrogenase-deficient RCC, mucinous-poor tubular and spindle cell carcinoma, and the oncocytic variant of the epithelioid angiomyolipoma. In conflictive cases, an immunohistochemical panel should help to solve the diagnostic problem. Therefore, the presence of abundant foamy macrophages should not dissuade the pathologist from establishing a diagnosis of RO. Prominent xanthomatous reaction despite its low frequency (4.3%) can be considered an additional feature of RO. Thus, RO should be added to the list of renal tumors that can show a significant reaction of lipid-laden foamy macrophages. Besides, Gamna–Gandy bodies can be present in this tumor.

Mycobacterium tuberculosis Infection-Driven Foamy Macrophages and Their Implications in Tuberculosis Control as Targets for Host-Directed Therapy

Tuberculosis (TB) is a leading cause of death worldwide following infection with Mycobacterium tuberculosis (Mtb), with 1.5 million deaths from this disease reported in 2018. Once the bacilli are inhaled, alveolar and interstitial macrophages become infected with Mtb and differentiate into lipid-laden foamy macrophages leading to lung inflammation. Thus, the presence of lipid-laden foamy macrophages is the hallmark of TB granuloma; these Mtb-infected foamy macrophages are the major niche for Mtb survival. The fate of TB pathogenesis is likely determined by the altered function of Mtb-infected macrophages, which initiate and mediate TB-related lung inflammation. As Mtb-infected foamy macrophages play central roles in the pathogenesis of Mtb, they may be important in the development of host-directed therapy against TB. Here, we summarize and discuss the current understanding of the alterations in alveolar and interstitial macrophages in the regulation of Mtb infection-induced immune responses. Metabolic reprogramming of lipid-laden foamy macrophages following Mtb infection or virulence factors are also summarized. Furthermore, we review the therapeutic interventions targeting immune responses and metabolic pathways, from in vitro, in vivo, and clinical studies. This review will further our understanding of the Mtb-infected foamy macrophages, which are both the major Mtb niche and therapeutic targets against TB.

Regulation of Macrophage Foam Cell Formation During Nitrogen Mustard (NM)-Induced Pulmonary Fibrosis by Lung Lipids.

Nitrogen mustard (NM) is a vesicant known to target the lung, causing acute injury which progresses to fibrosis. Evidence suggests that activated macrophages contribute to the pathologic response to NM. In these studies, we analyzed the role of lung lipids generated following NM exposure on macrophage activation and phenotype. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in a time-related increase in enlarged vacuolated macrophages in the lung. At 28 days postexposure, macrophages stained positively for Oil Red O, a marker of neutral lipids. This was correlated with an accumulation of oxidized phospholipids in lung macrophages and epithelial cells and increases in bronchoalveolar lavage fluid (BAL) phospholipids and cholesterol. RNA-sequencing and immunohistochemical analysis revealed that lipid handling pathways under the control of the transcription factors liver-X receptor (LXR), farnesoid-X receptor (FXR), peroxisome proliferator-activated receptor (PPAR)-ɣ, and sterol regulatory element-binding protein (SREBP) were significantly altered following NM exposure. Whereas at 1-3 days post NM, FXR and the downstream oxidized low-density lipoprotein receptor, Cd36, were increased, Lxr and the lipid efflux transporters, Abca1 and Abcg1, were reduced. Treatment of naïve lung macrophages with phospholipid and cholesterol enriched large aggregate fractions of BAL prepared 3 days after NM exposure resulted in upregulation of Nos2 and Ptgs2, markers of proinflammatory activation, whereas large aggregate fractions prepared 28 days post NM upregulated expression of the anti-inflammatory markers, Il10, Cd163, and Cx3cr1, and induced the formation of lipid-laden foamy macrophages. These data suggest that NM-induced alterations in lipid handling and metabolism drive macrophage foam cell formation, potentially contributing to the development of pulmonary fibrosis.

Clinicopathological Spectrum of Xanthogranulomatous Pyelonephritis.

Xanthogranulomatous pyelonephritis (XGP) is an uncommon and distinct type of chronic infective pyelonephritis causing destruction of the kidney, severely affecting the renal function. The perinephric adipose tissue and peritoneum is not uncommonly involved. The study was undertaken to decipher the clinicopathologic spectrum of XGP. Forty cases of XGP were diagnosed on histopathology over a period of 13 years (2005–2017). Relevant clinical details and radiological findings were recorded from the case files. Out of a total of 40 cases, 26 were female and 14 were male with a mean age of 39.5 ± 13.6 years. Flank pain was the most common presenting symptom. All the patients had unilateral disease and underwent nephrectomy for a nonfunctional kidney. Gross examination showed enlarged kidney with replacement of cortico-medullary tissue by yellow nodular areas of fatty tissue and dilatation of the pelvicalyceal system. Thirty-six (90%) cases had nephrolithiasis. Histologically, the characteristic feature was the existence of lipid-laden foamy macrophages. Renal parenchymal involvement was diffuse in majority (31, 77.5%). Two (5.0%) of the patients had coexisting carcinoma in the same kidney. Histopathologic examination gives the definitive diagnosis of XGP which relies on the characteristic morphology. Surgical intervention in the form of nephrectomy is the treatment of choice and offers good treatment outcomes.

Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models.

Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis. We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima. Single-cell RNA sequencing analysis of CD45+ leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYhiSSChi foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1β and many other inflammatory transcripts in atherosclerotic aorta. RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.

What Do Experimental Models Teach Us About Comorbidities in Stroke?

There is a general consensus that animal models do not perfectly represent human conditions. This is not derived from any specific event, such as an ischemic episode, but rather reflects inherent differences in the physiology, anatomy, and metabolism among different species. Disparities among species also arise from differences in assessing functional recovery in stroke. Humans place a priority in regaining function in speech, cognition, and limb control, but these functions are not always readily translatable in animal models. Moreover, because functional recovery depends on the stroke type and location, induction of an ischemic lesion in a predefined area of an animal model, at best, reflects only a subtype of human stroke. Nevertheless, certain clinical pathophysiology features of stroke, such as acute outcomes and inflammatory/immune responses, are shared in animal models.1 Combined with complementary knowledge from in vitro studies, animal models can provide valuable insight into stroke pathology at a systems level. Analyses of translational inefficiencies in stroke model systems have led to the identification of underlying issues, which include, but are not limited to, rigor in experimental design, internal and external validity, negative bias, and insufficient statistical power. Together, these inefficiencies have steered collaborative international efforts in preclinical research to overcome these challenges.2 An additional issue of importance is the insufficient understanding of stroke pathophysiology beyond the acute phase and the primary reliance on infarct volume in reporting acute outcomes. Together with a lack of inclusion of comorbidities in animal models of stroke, the development of clinical protocols based on findings from normal metabolic animals may contribute to translational failures. In light of a recent concerted effort to address the future of translational stroke research,3 this review focuses on underlying translational issues and discusses insights gained from stroke models inclusive of comorbidities in the preclinical literature. ### Stroke Pathology: A Moving Target With Multiple Components Despite …

Characterization of the Macrophage Infiltrate in a Case of Xanthogranulomatous Pyelonephritis.

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic infectious process of the kidney that results in diffuse destruction of the renal parenchyma [1,2]. The majority of cases of XGP occur in the setting of obstructing nephrolithiasis and are histologically characterized by the presence of lipid-laden foamy macrophages. To date, little is known regarding the molecular and functional phenotype of the infiltrating macrophages observed in cases of XGP. Human CD14+ monocytes can differentiate into macrophages and then become polarized towards two distinct phenotypes [3–5]. Classically activated (also known as M1) macrophages have the ability to secrete pro-inflammatory cytokines such as IFN-γ, IL-2, and TNF-α. Conversely, alternatively activated (also known as M2) macrophages secrete anti-inflammatory cytokines such as IL-10, IL-23, and VEGF. Characterization of the immune infiltrate in cases of XGP is necessary for understanding the pathogenesis of this disease process. Moreover, this knowledge may form the basis of future non-invasive treatment strategies for XGP. Herein, we report the phenotypic characterization of the macrophage infiltrate in a case of XGP.