Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 290 references
Medicine
TL;DR
It is shown that chronic inflammatory signaling can ultimately trigger a profound coordinated negative-feedback program consistent with a reduced immune recognition and defense pathway signatures, and offers deeper insights into how chronic inflammation impairs host defenses against viral and tumor cells.
Abstract
Introduction Chronic inflammation has long been associated with cancer initiation, yet the mechanisms linking sustained immune activation to an immune-permissive tumor microenvironment remain incompletely defined. Prevailing explanations such as immune exhaustion (IEX) or free radical mediated tissue damage, fail to account for the active state of immune tolerance, a process driven by potent negative feedback loops that systematically suppress host effector responses. Methods To address this gap, we developed an in vitro model of macrophage tolerance driven by sustained Toll-like receptor 4 (TLR4) activation using microbial-associated molecular patterns (MAMPs). This system captures the full kinetic progression of the immune response, tracking macrophages from a resting baseline, through acute activation at 24 hours, to a chronic tolerant endpoint at 7–11 days. Methodologically, cells were maintained under a continuous media exchange (+/− E. coli O111:B4 LPS) featuring high glucose and an elevated volume-to-cell ratio. This setup effectively eliminates autocrine interference and toxic byproducts, successfully isolating the direct consequences of sustained TLR4 signaling across extended durations. Results Whole-transcriptome sequencing, validated by RT-PCR and select protein immunoblots, revealed that both “exhaustion” and “tolerance” are mischaracterized. Rather than a passive exhaustion state or a simple trajectory of diminishing returns, the resting-acute-chronic continuum drives a potent, active negative-feedback mechanism across an eight-phase bidirectional trajectory. By days 7–11, macrophages shifted to a TAM-like signature, overexpressing immune checkpoints (PD-L1/MSN, TIM-3, SPP1, CD73, CD44, LILRs) and regulatory suppressive networks (SOCS/JAK/STAT, IL-10, CCL2/7/12, CXCL2), while downregulating classical (H2-D1/K1) and non-classical (H2-Q/T) MHC-I antigen-presenting genes. These alterations coincided with the profound loss of interferon-stimulated genes (ISGs) including the IFIT family, Ly6e, Irf7, Rsad2/Viperin, and the Oas gene family, fundamentally crippling the machinery required for antiviral and antitumor immune surveillance. Moreover, this chronic stage drove the upregulation of degradative proteases (cathepsins, Adam8, S100a8, Klk9, carboxypeptidase D), integrins/adhesion molecules (Itga5, Marcks, Msr1/CD204, Alcam), iron-storage transcripts, lipid translocases (Cd36), and fatty acid-binding proteins. Concurrently, macrophages upregulated Nos2/Cox2 alongside the metabolic collapse of mitochondrial OXPHOS genes and Acod1 (itaconate). Uniquely, this negative feedback loop coincided with a sustained, massive surge in a cluster of poorly characterized small proline-rich proteins (SPRRs), specifically Sprr2b, 2e, 2d, 2f, 2g, 2h, 2i, 2j, and 2k. Discussion Overall, these results indicate that chronic inflammatory signaling can ultimately trigger a profound coordinated negative-feedback program consistent with a reduced immune recognition and defense pathway signatures. Ultimately, this study provides a reproducible in vitro macrophage model to investigate immune suppression. It offers deeper insights into how chronic inflammation impairs host defenses against viral and tumor cells.
Neutrophils, traditionally viewed as short-lived, terminally differentiated innate immune cells with no capacity for immunological memory, have recently been recognized as key players in trained immunity. This concept challenges the classical dichotomy between innate and adaptive immunity by demonstrating that prior microbial or inflammatory stimuli can induce long-lasting functional reprogramming of innate immune cells. This review provides a comprehensive overview of neutrophil-trained immunity, covering the central role of the bone marrow niche in storing innate immune memory, the epigenetic and metabolic mechanisms that underpin training, the diverse triggers (microbial ligands, vaccines, and endogenous sterile inducers), and the resulting functional consequences in neutrophils. Crucially, this response operates on a dose-dependent polarity: low-dose priming induces protective memory, whereas chronic or excessive inflammatory stimuli trigger neutrophil exhaustion and persistent tissue injury. We argue that the classical paradigm of autoantibody-driven tissue damage in autoimmune conditions is fundamentally anchored by "maladaptive trained immunity" established at the central hematopoietic level. Finally, this review discusses new strategies for the preparation of trained immunity-based vaccines and adjuvants, enhancement of immunity in immunocompromised patients, and clinical treatment to inhibit chronic inflammation, while also highlighting research gaps regarding the durability of neutrophil-trained immunity, the potential for de-training, and the interplay between trained immunity and other immune components, thereby revealing the significant implications and research prospects of neutrophil-trained immunity.
Fumei Liu, Jiatong Chai, Peini Yang et al.· Autoimmunity Reviews· 0 citations
Chronic viral infections pose significant challenges to host immunity, often leading to viral persistence and suppressed immune responses. These infections are characterized by prolonged antigen exposure, progressive T cell dysfunction, and complex interactions between innate and adaptive immune compartments. While extensive research has delineated mechanisms of CD8⁺ T cell exhaustion, the molecular pathways governing the suppression of CD4⁺ T cells and innate immune cells in chronic viral infection remain incompletely understood. Moreover, the role of metabolic signaling in shaping immune responses during chronic infection is increasingly recognized but poorly defined. Sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid metabolism, has emerged as a potential metabolic checkpoint that integrates immune regulation with host antiviral responses. Using the chronic lymphocytic choriomeningitis virus (LCMV) Clone 13 infection mouse model, this dissertation investigates the dual role of SphK2 in modulating immune responses across both the adaptive and innate compartments. The first part focuses on CD22, one of the downstream regulators of SphK2, identifying the SphK2-CD22 axis as an important pathway that suppresses virus-specific CD4⁺ T cell proliferation and effector function. The second part examines SphK2-mediated control of innate immunity, revealing that neutrophils acquire suppressive phenotypes under the influence of SphK2, thereby partially limiting immune-mediated pathology. These studies collectively demonstrate that SphK2 functions as a central metabolic regulator that coordinates T cell-intrinsic and myeloid cell-mediated immune pathways during chronic viral infection. By integrating functional immunological assays, adoptive transfer experiments, and transcriptomic analyses, this work provides mechanistic insights into how SphK2 intersects with immune suppression and viral persistence. Understanding these pathways may inform the development of novel therapeutic strategies aimed at restoring antiviral immunity while minimizing immunopathology in chronic viral diseases.
This emerging view frames exhaustion as a context-dependent extension of the memory program rather than its collapse, and highlights how these insights can inform new approaches to manipulate T cell fate for therapeutic benefit.
Daniel T. Utzschneider, Stephen J. Turner· Trends in immunology· 0 citations
The viral reservoir established after HIV-1 infection remains the primary barrier to curing HIV. Recent studies suggest that proviral HIV-1 DNA, low-level viral transcripts, and other reservoir-derived viral products may contribute to persistent innate immune activation and type I interferon (IFN-I)-related inflammatory programs. This sustained activation drives a state of chronic immune activation, which induces and maintains exhaustion in immune cells such as CD4
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T cells. Exhaustion is characterized by loss of effector function and upregulation of inhibitory receptors (immune checkpoints), severely compromising the host’s antiviral immune response. In this review, we systematically examine the molecular and cellular mechanisms by which the HIV-1 reservoir fuels immune exhaustion through the IFN-I signaling pathway. We further explore potential intervention targets along this pathway, providing a theoretical framework for the development of novel therapeutic strategies aimed at reservoir elimination or reversal of immune exhaustion.
Zhihui Zhang, Peng-Fei Ren, Meng Deng et al.· Frontiers in Immunology· 0 citations
Inflammatory disease is sustained not only by immune activation but also by the failure of activated cells to terminate effector programs and return tissues to homeostasis. This review evaluates N
6
-methyladenosine (m
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A) as a post-transcriptional regulator of that persistence. Rather than cataloguing diseases or classifying individual m
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A regulators as pro- or anti-inflammatory, we organize the evidence around a causal chain linking a regulator and target RNA to a site- or reader-dependent change in RNA fate, an immune-cell phenotype, and a disease outcome. Mechanistically developed evidence is concentrated in macrophages and T cells, including STAT1 stability and decay, SOCS turnover, SLC37A2 translation, and lineage-specific T-cell programs. Mechanisms in other innate and adaptive immune populations are emerging, but cell-subset resolution and disease-stage validation remain uneven. Across inflammatory signaling, immunometabolic, and cell-death pathways, the same m
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A regulator can produce opposing outcomes through different target transcripts or readers. We therefore distinguish mechanistically resolved, functional/intermediate, and associative evidence while highlighting the limitations of global m
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A assays, bulk-tissue profiling, and pathway-level inference. The translational value of m
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A is likely to depend on target-RNA selection, cell-specific delivery, disease-stage timing, and preservation of protective immunity and tissue repair. An evidence-aware, transcript-centered framework may help move m
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A research from descriptive association toward causal immune-state biology and clinically testable interventions.
Unknown authors· Frontiers in Immunology· 0 citations
ABSTRACT Mycobacterium tuberculosis (Mtb) remodels host cell functions to support its persistence within macrophages. While infected cells have been extensively studied, the responses of uninfected bystander macrophages in the same microenvironment remain poorly understood. Here, we demonstrate that Mtb infection triggers broad epigenetic and transcriptional reprogramming in bystander macrophages, predominantly via interleukin-1β-dependent nuclear factor-κB signaling from infected cells. These bystander cells acquire active chromatin marks, exhibit distinct gene expression profiles, and display enhanced responsiveness to subsequent immune challenges. Functionally, bystander macrophages restrict intracellular Mtb growth and also show increased responsiveness to heterologous stimuli resembling trained immunity. Our findings uncover a previously underappreciated mechanism of intercellular communication during infection, wherein Mtb-infected macrophages prime neighboring uninfected cells for enhanced defense. This work defines cytokine-mediated reprogramming of both infected and bystander cell subpopulations, and identifies bystander cells as active participants in shaping the population-wide host immune landscape. These insights have implications for understanding innate immune memory and developing strategies to modulate host defense in tuberculosis and other infections. IMPORTANCE This study reveals an underappreciated role for uninfected bystander macrophages in host defense against Mycobacterium tuberculosis (Mtb). We demonstrate that Mtb-infected macrophages trigger interleukin-1β-mediated epigenetic training in neighboring bystander cells, priming them for enhanced immune responses. These trained macrophages exhibit heightened antimicrobial activity and restrict Mtb growth upon subsequent infection. By uncovering a mechanism through which immune memory-like responses propagate beyond infected cells, our findings redefine the cellular scope of innate immunity during tuberculosis and identify new opportunities to boost host defense through intercellular signaling and epigenetic reprogramming. This study reveals an underappreciated role for uninfected bystander macrophages in host defense against Mycobacterium tuberculosis (Mtb). We demonstrate that Mtb-infected macrophages trigger interleukin-1β-mediated epigenetic training in neighboring bystander cells, priming them for enhanced immune responses. These trained macrophages exhibit heightened antimicrobial activity and restrict Mtb growth upon subsequent infection. By uncovering a mechanism through which immune memory-like responses propagate beyond infected cells, our findings redefine the cellular scope of innate immunity during tuberculosis and identify new opportunities to boost host defense through intercellular signaling and epigenetic reprogramming.
Shah-e-Jahan Gulzar, Ibrahim A. Umar, Bharath Saravanan et al.· mBio· 0 citations