The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+ mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+ MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1. Genetic depletion of ADAM12+ cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+ MSCs through ADAM12 restores antitumor immunity.
© 2023. The Author(s).

Germinal centers (GCs) are sites where plasma and memory B cells form to generate high-affinity, Ig class-switched antibodies. Specialized stromal cells called follicular dendritic cells (FDCs) are essential for GC formation. During systemic Salmonella Typhimurium (STm) infection GCs are absent, whereas extensive extrafollicular and switched antibody responses are maintained. The mechanisms that underpin the absence of GC formation are incompletely understood. Here, we demonstrate that STm induces a reversible disruption of niches within the splenic microenvironment, including the T and B cell compartments and the marginal zone. Alongside these effects after infection, mature FDC networks are strikingly absent, whereas immature FDC precursors, including marginal sinus pre-FDCs (MadCAM-1+) and perivascular pre-FDCs (PDGFRβ+) are enriched. As normal FDC networks re-establish, extensive GCs become detectable throughout the spleen. Therefore, the reorganization of FDC networks and the loss of GC responses are key, parallel features of systemic STm infections.
© 2023 The Authors.

Microglia are the resident innate immune cells of the central nervous system (CNS) parenchyma. To determine the impact of microglia on disease development and progression in neurodegenerative and neuroinflammatory diseases, it is essential to distinguish microglia from peripheral macrophages/monocytes, which are eventually equally recruited. It has been suggested that transmembrane protein 119 (TMEM119) serves as a reliable microglia marker that discriminates resident microglia from blood-derived macrophages in the human and murine brain. Here, we investigated the validity of TMEM119 as a microglia marker in four in vivo models (cuprizone intoxication, experimental autoimmune encephalomyelitis (EAE), permanent filament middle cerebral artery occlusion (fMCAo), and intracerebral 6-hydroxydopamine (6-OHDA) injections) as well as post mortem multiple sclerosis (MS) brain tissues. In all applied animal models and post mortem MS tissues, we found increased densities of ionized calcium-binding adapter molecule 1+ (IBA1+ ) cells, paralleled by a significant decrease in TMEM119 expression. In addition, other cell types in peripheral tissues (i.e., follicular dendritic cells and brown adipose tissue) were also found to express TMEM119. In summary, this study demonstrates that TMEM119 is not exclusively expressed by microglia nor does it label all microglia, especially under cellular stress conditions. Since novel transgenic lines have been developed to label microglia using the TMEM119 promotor, downregulation of TMEM119 expression might interfere with the results and should, thus, be considered when working with these transgenic mouse models.
© 2022 The Authors. GLIA published by Wiley Periodicals LLC.

Helicobacter suis, a zoonotic infection-related bacterium, induces gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. However, a lack of suitable animal models complicates the detailed analysis of this disease. Here, we describe the generation of a gastric MALT lymphoma mouse model. We then detail the use of this model combined with an immunostaining protocol to identify the cell populations that constitute gastric MALT lymphoma. This protocol can be used to identify the constituent cells of human MALT lymphoma. For complete details on the use and execution of this profile, please refer to Yamamoto et al. (2021).
© 2022 The Author(s).

Helicobacter suis, a zoonotic infection-related bacterium, can induce gastric mucosa-associated lymphoid tissue (MALT) lymphoma in humans and animals. Recently, we reported that the formation of gastric MALT lymphoma after H. suis infection is induced by interferon (IFN)-γ activation. Here, we revealed that activation of the Toll-like receptor (TLR) 4-Toll/IL-1 receptor domain-containing adapter-inducing interferon-β (TRIF) pathway after H. suis infection is associated with the production of type 1 IFNs (IFN-α, IFN-β) by gastric epithelial cells. Additionally, these type 1 IFNs interact with type 1 IFN receptors on gastric B cells, facilitating the secretion of IFN-γ and the activation of which is enhanced by positive feedback regulation in B cells. These results suggest that the TLR4-TRIF-type 1 IFN-IFN-γ pathway is crucial in the development of gastric MALT lymphoma after H. suis infection and may, therefore, represent a therapeutic target for the prevention of this condition.
© 2021 The Author(s).