Granulomas and Disease
What happens when the macrophage cannot finish eating. Foreign body, TB, sarcoid, and histiocytic neoplasms: their biology, their morphology, and what distinguishes them.
Granuloma barrier integrity requires coordinated junctional, cytoskeletal, and ECM gene networks in macrophages; failure breaches containment. Largemouth bass (Micropterus salmoides) Nocardia seriolae model.
Epithelioid macrophages in established granulomas upregulate OXPHOS and glycolysis genes with mitochondrial proliferation; immune regulation sustains the structure over time. Largemouth bass (Micropterus salmoides) Nocardia seriolae model.
Comprehensive review of granuloma etiologies on histopath; diagnostic challenges and emerging approaches including molecular profiling.
NOX2 deficiency (CGD): type 1 and type 3 immune responses drive granuloma formation. The granulomas form because the macrophage cannot finish the kill.
RDD can mimic BRAF+ histiocytosis on molecular testing. Emperipolesis on H&E remains the morphologic anchor. Never skip the H&E.
Full text of the genomics review; BRAF, MAP2K1, KRAS, ALK frequency tables across LCH/ECD/RDD.
LPCAT2 in granuloma macrophages is ontogeny-independent: local activation drives phenotype, not cell origin.
Methotrexate noninferior to prednisone as first-line pulmonary sarcoidosis treatment (PREDMETH trial, NEJM 2025); signals a shift in standard practice.
Kupffer cells, classically regarded as terminally differentiated, show plasticity during mycobacterial infection; hepatic granuloma outcome depends on this reprogramming capacity.
Tofacitinib (JAK3 inhibitor) reduces sarcoid granuloma burden in a SodA-induced model by restoring Treg function and shifting macrophages toward M2 via JAK3/STAT5.
PTX3-driven M2 polarization of macrophages enhances efferocytosis and resolves inflammation in granulomatous mastitis; PTX3 signaling as a therapeutic target in granulomatous disease.
Mycobacterial mycolic acids disrupt cholesterol trafficking in macrophages, causing cholesterol and MHC class II to accumulate in lysosomes rather than at the surface; in necrotic granulomas this impairs CD4+ T cell activation and infection control. Nature Microbiology 2026.
2026 review covering the full aetiological spectrum of granulomatous inflammation (infectious, autoimmune, foreign body, neoplastic) with attention to diagnostic pitfalls in histopathological interpretation and future directions for classification. Ann Med 2026.
SPIC transcription factor defines a distinct erythrophagocytic macrophage subset that paradoxically supports granuloma formation and intracellular bacterial persistence (Salmonella); macrophage identity, not just activation state, shapes granuloma permissiveness. Preprint.
Post-TB sequelae (fibrotic scarring, cavitation, bronchiectasis) sustain chronic inflammation and oxidative DNA damage that promote oncogenesis; 2-3x increased lung cancer incidence after pulmonary TB, persisting years beyond cure. Frontiers Immunol 2026.
scRNA-seq analysis of sarcoidosis and tattoo uveitis identifies 506 granuloma-associated genes and ten immune signaling pathways driving non-caseating granuloma formation; pseudotime trajectory and intercellular communication networks mapped. In-silico study; validation in larger cohorts needed.
2025 review of cutaneous histiocytoses (LCH, ECD, RDD, and rarer entities) covering polymorphous cutaneous presentations, IHC panel requirements, BRAF/RAF-MEK-ERK mutation landscape, and diagnostic pitfalls; notes that cutaneous involvement can be primary or a window into multisystem disease. Frontiers in Medicine 2025.
Retrospective cohort (34 patients); interstitial pattern predominant (64.7%); universal mucin deposition; giant cell presence correlates positively with lesion duration, establishing giant cell formation as a histopathological marker of granuloma remodeling over time. Diagnostics 2026.
Legumain (LGMN) binds integrin alphavbeta3 on macrophages, dampening mTORC1/STAT1 signaling to limit M1 polarization and granuloma formation in sarcoidosis; intratracheal lipid nanoparticle delivery of Lgmn plasmid attenuates disease in mice.
Flow cytometry study identifying M1 macrophage activation (CD8a+CD45+) as a diagnostic biomarker with high specificity for active sarcoidosis; iNKT cells (CD3+CD56+CD16+) as independent negative prognostic predictor; granuloma composition maps to measurable circulating populations. July 2026.
Visium spatial transcriptomics across 173 granulomas from 9 sarcoidosis lung explants; CD68+ macrophage niche at granuloma center forms an armed-and-ready hybrid pro-inflammatory/pro-fibrotic state; sustained IFN-gamma stimulation and peripheral COL3A1+ fibroblast niche maintain chronicity. Am J Respir Crit Care Med 2026.
Patient-derived organoids with intact TME; anti-CD47 checkpoint blockade stimulates macrophage phagocytosis but reprograms TAMs toward immunosuppressive SPP1+ state; demonstrates a negative feedback loop limiting the benefit of "don't eat me" signal blockade. 2026 preprint.
CD68+ multinucleated giant cells in ~28% of pancreatic tumors; lack canonical M1/M2 polarization markers; carry DNA damage response signatures; correlate with worse outcomes in aggressive subtypes. Cancer Immunol Res 2026.
Mucosal Immunology 2026: in primate TB granulomas, tissue-resident alveolar macrophages, monocyte-derived alveolar macrophages, and interstitial macrophages show distinct spatial localization and differential Mtb infection rates; identifies subset with epithelial-to-mesenchymal transition signature as preferentially targeted.
Hum Pathol 2026: systematic review of non-LCH histiocytoses including Erdheim-Chester disease, Rosai-Dorfman disease, and emerging entities; clinical, pathological, and molecular heterogeneity; MAPK/ERK pathway mutations common across subtypes; diagnostic challenges and evolving classification.
Am J Physiol Cell Physiol 2025: spatial mass spectrometry imaging (MALDI-MSI) identifies eight conserved lipid signatures in both murine sarcoid-like granulomas and human sarcoidosis tissue; shared metabolic fingerprint across species suggests intrinsic lipid remodeling as a feature of granulomatous inflammation and opens metabolic biomarker avenues.
Cell Host Microbe 2026: leukotriene A4 hydrolase (LTA4H)-dependent eicosanoid signals recruit a specialized fibroblast population to mycobacterial granulomas; this fibroblast layer coordinates containment and limits bacterial dissemination; links host LTA4H genetic variation to TB susceptibility through stromal-macrophage crosstalk at the granuloma boundary.
Am J Pathol 2026: low-dose radiotherapy reduces TB granuloma burden by activating ATM kinase, which suppresses interferon-beta and shifts macrophage response toward resolution; ATM agonist GJ071 oxalate reproduces therapeutic benefit without radiation; repurposes an established DDR pathway as a granuloma resolution target.
Am J Respir Crit Care Med 2026: MMP12 acts as a macrophage-intrinsic inducer of fibrogenic differentiation within cardiac sarcoidosis granulomas; blocking MMP12 disrupts granuloma architecture and reduces myocardial fibrosis in mouse models; identifies MMP12 as a macrophage-driven molecular link between granulomatous inflammation and fibrotic remodeling.
Am J Respir Crit Care Med 2026: editorial commentary on the granuloma-to-fibrosis transition in cardiac sarcoidosis; discusses how macrophage populations and molecular pathways (including MMP12) mechanistically connect granulomatous inflammation to progressive myocardial fibrosis.
Int Immunopharmacol 2026: CXCR6+ CD4+ T cells adopt Th17/Th17.1 phenotype in sarcoidosis lesions; anti-CXCR6 treatment reduces inflammatory cell recruitment, suppresses granuloma formation, and attenuates lung fibrosis; T cell-macrophage axis mediated through CXCR6 chemokine signaling as a therapeutic target.