Pulmonary arterial hypertension (PAH) is sustained by pulmonary vascular remodeling and right ventricular (RV) maladaptation that often remain incompletely reversible despite contemporary pathway-directed therapy. A central mechanistic question is how macrophage states that promote remodeling are maintained. This focused narrative review examines three potentially coexisting explanations: continued conditioning by the pathological niche, selective recruitment of monocyte subsets with pre-existing inflammatory signatures, and cell-intrinsic regulatory states that persist after stimulus withdrawal. Single-cell and spatial studies identify lesion-, subset- and stage-dependent macrophage states, but cannot alone distinguish these explanations. Metabolic regulation of chromatin and RNA provides candidate links between local cues and sustained function. We compare TET2-dependent DNA regulation and METTL3/m6A-dependent RNA fate as complementary routes through which metabolic cues may influence inflammatory restraint and effector output. Human associations and hematopoietic or myeloid perturbation studies support their investigation, but do not establish durable programming in human lesional macrophages. We therefore distinguish ongoing activation from persistent programming and trained immunity, evaluate pulmonary and RV evidence separately, and define the validation requirements for testing whether disruption of macrophage-state maintenance can reverse established disease.
Listeria monocytogenes, a facultative intracellular bacterium that causes listeriosis, infects the host primarily through contaminated food. After translocating across the intestinal epithelium, L. monocytogenes multiplies and spreads to secondary organs, such as the liver and spleen. While L. monocytogenes employs multiple mechanisms to invade host tissues, survive within host cells, and modulate immune responses, the host mounts coordinated innate and adaptive immune responses to restrict bacterial dissemination and establish protective immunity. In Peyer’s patches (PPs), a subset of mononuclear phagocytes termed LysoDCs captures bacteria translocated through M cells and contributes to the induction of Listeria-specific T-cell responses. Adaptive immune responses in PPs and mesenteric lymph nodes (MLNs), particularly CTL and Th1 responses, contribute to the establishment of long-term protection. Inflammatory monocytes are recruited to infected tissues, including the intestine and liver, where they contribute to bacterial control through antimicrobial effector mechanisms, including the production of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α). In this review, we summarize the mechanisms underlying intestinal invasion by L. monocytogenes, bacterial strategies that interfere with host defense, and the immune responses that control infection from the intestinal mucosa to systemic organs, particularly the liver. We focus on immune responses in PPs and MLNs and the mechanisms regulating inflammatory monocyte trafficking and function during L. monocytogenes infection. We also discuss recent findings showing that the pyruvate–GPR31 axis promotes dendrite extension by LysoDCs into M-cell pockets and facilitates bacterial sampling, whereas GPR35 promotes recruitment of inflammatory monocytes from the circulation into infected tissues. Together, these findings highlight immune-cell positioning and trafficking as important components of the spatial and temporal coordination of host defense against L. monocytogenes.
Chronic low-grade systemic inflammation serves as a pivotal pathological link coupling unhealthy lifestyles with malignant remodeling of body composition. This review systematically constructs and elucidates the molecular mechanisms and pathological progression of the “lifestyle-immunometabolic-neuroendocrine” crosstalk network in ectopic fat deposition and skeletal muscle decline. Upstream multidimensional lifestyle stressors—including unhealthy diets, sleep deprivation, psychological stress, and sedentary behavior—disrupt the gut barrier, endocrine barriers, and mechanical contractile strain, thereby initiating immunometabolic reprogramming and triggering systemic chronic low-grade sterile inflammation. Acting as a core pathological driver, this low-grade inflammation impairs lipid and protein homeostasis, propels lipotoxic spillover and intramyocellular fat infiltration, and ultimately leads to the progressive decline of skeletal muscle mass and function. Concurrently, age-related neuroendocrine axis decline and dwindling sex hormone levels function as endogenous amplifiers, synergistically accelerating tissue microenvironmental remodeling and body composition imbalance in a distinctly dimorphic manner (e.g., postmenopausal estrogen deficiency accelerates muscle deterioration by inducing autophagy dysfunction in muscle stem cells). A deep mechanistic parsing of the regulatory nodes within this multidimensional network provides substantial academic value for deciphering the onset and progression of lifestyle-driven chronic inflammatory disorders.
Primary and metastatic brain tumors remain among the most challenging malignancies to treat, with limited therapeutic options and poor clinical outcomes despite substantial advances in cancer immunotherapy. Although immune checkpoint blockade (ICB) and other immunotherapies have transformed the treatment landscape for many cancers, they have demonstrated only limited efficacy in brain tumors. This limited responsiveness reflects the unique immune landscape of the central nervous system (CNS), which restricts immune cell infiltration and is further shaped by a highly immunosuppressive tumor immune microenvironment (TIME) that suppresses effective antitumor immunity. Consequently, therapeutic strategies capable of enhancing tumor immunogenicity while overcoming local immune suppression are urgently needed. One promising approach is the induction of immunogenic cell death (ICD), a form of regulated cell death that stimulates anti-tumor immunity through the release of danger-associated molecular patterns (DAMPs), tumor antigens, and inflammatory cytokines and chemokines that promote immune activation. However, the ability of ICD to generate durable antitumor responses within brain tumors is therefore likely influenced by the complex immunosuppressive networks that characterize the brain TIME. In this review, we examine the major barriers to effective antitumor immunity within brain tumors, focusing on the immunosuppressive cellular and cytokine/chemokine molecular networks that shape the brain tumor immune microenvironment, the influence of tumor origin and subtype on immune composition, and the implications of these features for therapeutic responsiveness. We then discuss how ICD may help overcome these barriers by enhancing antigen presentation, immune cell recruitment, and adaptive immune priming. We review the principal ICD-associated cell death modalities, including ferroptosis, necroptosis, and pyroptosis, and summarize current therapeutic approaches capable of inducing these pathways in brain tumors, including radiotherapy, chemotherapy, targeted therapies, oncolytic viruses, and emerging nanomedicine-based strategies. Finally, we highlight clinical and preclinical evidence supporting ICD-relevant therapeutic approaches across glioblastoma (GBM) and brain metastases and discuss rational combination strategies may improve immune responsiveness and therapeutic outcomes in patients.
Prohibitin 2 (PHB2) has been linked to mitochondrial inner-membrane organization, mitophagic recognition, receptor-associated signaling and nuclear transcription. Treating these observations as functions of a single uniform protein entity obscures important differences in localization, PHB1 dependence, membrane exposure and partner composition. Here, we use an evidence-based framework to distinguish context-defined PHB2 molecular states according to compartment or membrane topology, native-complex status and accessibility of defined molecular interfaces. Receptor-associated studies involving IGFBP6, grancalcin, SLAMF/B-cell receptor complexes, GALNT14-dependent IGF1R signaling and DDR2-TGFBR2 regulation support stimulus- and cell-restricted PHB2-containing systems, but do not establish a universal PHB2 surface receptor or a common trafficking route. Within mitochondria, crista architecture, respiratory competence and proteostasis are predominantly properties of the PHB1-PHB2 assembly, whereas damage-induced exposure of the PHB2 LC3-interacting region provides a subunit-specific mechanism for mitophagic recognition. PHB2 also contributes at distinct stages of PINK1-Parkin mitophagy, although the upstream PARL-PGAM5-PINK1 effect is less clearly separable from prohibitin-complex function than the mapped LIR-LC3 interaction. Divergent immune outcomes further vary with the mitochondrial cargo being removed and the experimental context: clearance of mitochondria that provide cytosolic mtDNA or other NLRP3-activating signals can limit inflammatory signaling, whereas turnover of MAVS-containing membranes can suppress type I interferon. Post-translational modifications regulate local PHB2 interactions or complex stability, but current evidence does not support a universal modification-driven trafficking program. Mechanistic and pharmacological studies should therefore define the relevant PHB2 state or molecular interface, verify native PHB1-PHB2 complex integrity and measure direct target engagement.
