Open research questions in Immune Response and Inflammation

What the literature leaves open

• In addition, no pharmacokinetic, biodistribution, or organ-specific safety studies were performed in the present work, and potential effects on the kidney, thyroid, and inner ear remain to be explored. Given that pendrin inhibitors significantly reduce key inflammatory cytokines such as IL-6, TNF-α, and IL-1β, they may warrant further investigation as novel therapeutics for pneumonia-induced ARDS.

  The comparison of two pendrin inhibitors, YS-01 and PDSinh-C01, in lipopolysaccharide-induced acute lung injury · 2026 · DOI

• It highlights the need to investigate the relationship between immune cells and inflammatory cytokines in the tumor microenvironment. The gap in understanding the critical roles of macrophages and cytokines in disease initiation, progression, and leukemic transformation is addressed.

  The role of macrophages and cytokines in the occurrence and development of MDS · 2026 · DOI

• Interactions with NK cells and regulatory T cells have not been systematically investigated. The capacity of these marine lectins to modulate the TME and enhance cancer immunotherapy in combination with checkpoint inhibitors has not been evaluated despite their demonstrated effects on macrophage polarization.

  Marine Lectins in Innate Immune Modulation: Mechanistic Insights, Signaling Pathways, and a Cross-Taxa Evidence Landscape · 2026 · DOI

• At the cellular level, how TLR-driven metabolic reprogramming is spatially and temporally coordinated with migratory machinery remains poorly understood.

  TLR Signaling Beyond Immunity: Emerging Roles in Cell Migration, Metabolism, Development, and Host–Microbiome Crosstalk · 2026 · DOI

• High-mobility group box 1 (HMGB1) may contribute to peripheral-central communication, but the role of lysozyme M (LysM)-expressing cells in circulating HMGB1 and compartment-specific inflammatory responses remains unclear.

  Tissue-specific inflammatory responses to systemic LPS in mice with LysM-lineage Hmgb1 deletion · 2026 · DOI

• One major challenge is systemic toxicity, which can hinder clinical outcomes. Advances in structural biology and structure–activity relationship (SAR) analyses have helped elucidate the molecular interactions of these agonists, paving the way for more targeted and safer designs. However, challenges remain.

  Enhancing Cancer Therapy with TLR7/8 Agonists: Applications in Vaccines and Combination Treatments · 2025 · DOI

• The mechanisms by which sex steroid hormones enhance HIV-1 replication are not fully understood, but the observed increase in HIV-1 RNA may be partially related to increased TLRs expression.

  Gonadocorticoids Have Different Effects on the Expression of Toll-like Receptors When Infected with Various HIV-1 Subtypes · 2025 · DOI

• Although the role of the intestinal immune system in protecting adult chickens from various enteric pathogens has been extensively studied, the reasons behind the increased susceptibility of newly hatched chicks to enteric infections remain unclear.

  Differential Expression of Key Immune Markers in the Intestinal Tract of Developing Chick Embryos · 2025 · DOI

• Future research will focus on further optimization of the FLA-ST adjuvant formulation and structure, as well as on dose-response relationship studies.

  Adjuvant Mucosal Strategies Confer Safe and Effective Immunity Against Mycoplasma pneumoniae and Overcome Vaccine-Associated Enhanced Lung Pathology · 2025 · DOI

• Persistent infection may be due to a lack of a response to viral antigens, functional unresponsiveness, or partial immune control that is insufficient to trigger immune-mediated regression. Regression is immune-mediated, but the trigger for regression is currently unknown.

  The Epithelial Immune Response to Human Papillomavirus Infection · 2025 · DOI

• Although its specific mechanism of action still needs to be further explored, it is worth noting that matrine could inhibit inflammatory responses, regulate intestinal oxidative stress levels, improve the intestinal barrier integrity, upregulate the Treg/Th17 ratio and play a powerful therapeutic role in UC.

  Matrine Ameliorates DSS-Induced Colitis by Suppressing Inflammation, Modulating Oxidative Stress and Remodeling the Gut Microbiota · 2024 · DOI

• Mouse models do have limitations when compared with human SLE. Even though humans and mice are quite similar, we do not share the same immune system, and it is thus not possible to directly transfer results from mice to humans. The same goes for tolerance and response to treatment.

  Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus · 2024 · DOI

• Further research is needed to elucidate the chemical structure and structure-activity relationship of LTA, - Future studies should analyze gene expression during the early stages of LTA treatment, - Further studies on HOM5301 LTA in gut-associated lymphoid tissue and in mice are required to better understand the mechanism of action of H.

  Lipoteichoic Acid from Heyndrickxia coagulans HOM5301 Modulates the Immune Response of RAW 264.7 Macrophages · 2024 · DOI

• The detailed molecular mechanisms of action of LTAs from different probiotic strains are not well understood. The structural heterogeneity of LTA leads to diverse immunostimulatory activities.

  Lipoteichoic Acid from Heyndrickxia coagulans HOM5301 Modulates the Immune Response of RAW 264.7 Macrophages · 2024 · DOI

• The need to understand the mechanisms underlying the divergent inflammatory responses to lipopolysaccharide and peptidoglycan in chickens. The lack of comprehensive studies on the local and systemic inflammatory responses of peptidoglycan in the chicken model.

  The Bacterial Cell Wall Components Lipopolysaccharide and Peptidoglycan Initiate Divergent Local Tissue and Systemic Inflammatory Response Profiles in the Chicken Model · 2024 · DOI

• The specific impacts of inflammation on dairy cows with a high-concentrate diet are yet to be determined. The mechanisms of cecropin A in alleviating inflammation are not fully understood.

  Cecropin A Alleviates LPS-Induced Oxidative Stress and Apoptosis of Bovine Endometrial Epithelial Cells · 2024 · DOI

• Whether other RTKs are activated in response to DSV remains to be determined. Further studies are needed to investigate whether other RTKs are involved in this process. Which component of DSV induces TLR 2 signaling remains to be determined. Whether or not H2S produced by DSV activates this pathway remains to be tested.

  Sulfate-Reducing Bacteria Induce Pro-Inflammatory TNF-α and iNOS via PI3K/Akt Pathway in a TLR 2-Dependent Manner · 2024 · DOI

• Several studies have reported that cigarette smoke (CS) exposure promotes pneumococcal infectivity; however, the underlying mechanisms remain to be illustrated.

  Cigarette smoke compromises macrophage innate sensing in response to pneumococcal infection · 2024 · DOI

• Future research should focus on further exploring the functional implications of these evolutionary findings and translating them into clinical applications, ultimately improving therapeutic outcomes and patient care.

  IL-1 Superfamily Across 400+ Species: Therapeutic Targets and Disease Implications · 2025 · DOI

• The findings suggest the therapeutic potential of probiotics, either on their own or in combination with immunotherapies, encouraging further investigation into treatments for osteolytic cancers.

  Natural Killer Cell Therapy Combined with Probiotic Bacteria Supplementation Restores Bone Integrity in Cancer by Promoting IFN-γ Production · 2025 · DOI

• While this experiment confirmed the beneficial role of BCFAs in alleviating inflammatory responses at the cellular level, the specific targets and mechanisms of action remain unclear.

  Alleviating the Effect of Branched-Chain Fatty Acids on the Lipopolysaccharide-Induced Inflammatory Response in Calf Small Intestinal Epithelial Cells · 2025 · DOI

• ENO1 is increasingly recognized as a moonlighting protein whose biological significance extends far beyond its canonical role in glycolysis. Throughout this review, ENO1 has been implicated in metabolic regulation, transcriptional control, RNA-associated processes, signaling, immune responses, extracellular interactions, and the regulation of pathogen replication.

  ENO1 functional plasticity linking metabolism with gene regulation and immunity at the host–pathogen interface · 2026 · DOI

• Many different mechanisms of action are used by each antigen to achieve antigen-specific antibody-mediated responses. However, the available data and studies cannot adequately explain the details of these mechanisms or help in deciding which mechanism is used in different contexts.

  Transcriptional Systems Vaccinology Approaches for Vaccine Adjuvant Profiling · 2025 · DOI

• Although sex was recorded for all participants, the study was not powered to detect sex-specific effects, and potential differences related to sex could not be assessed.

  TLR4 Asp299Gly SNP (rs4986790) Protects from Periodontal Inflammatory Destruction by Altering TLR4 Susceptibility to LPS Stimulation · 2025 · DOI

• Investigating the role of IL-1β in the occurrence and progression of MDS, - Studying the effects of IL-6 blockade on the clonality of CD34 + cells and progression to AML, - Examining the relationship between TNF-α and the pathogenesis…

  The role of macrophages and cytokines in the occurrence and development of MDS · 2026 · DOI

Most-cited papers in Immune Response and Inflammation

• Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene · Science · 1998 · 5,653 citations
• A Toll-like receptor recognizes bacterial DNA · Nature · 2000 · 5,087 citations
• Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 · Nature · 2001 · 4,985 citations
• Adhesion receptors of the immune system · Nature · 1990 · 4,880 citations
• Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response · Science · 2006 · 3,171 citations
• Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 · Science · 2004 · 3,146 citations
• CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and LPS Binding Protein · Science · 1990 · 2,973 citations
• The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 · Nature · 2001 · 2,835 citations
• HMG-1 as a Late Mediator of Endotoxin Lethality in Mice · Science · 1999 · 2,815 citations
• Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway · Science · 2003 · 2,593 citations

Most recent work

• Polymyxin B haemoadsorption in endotoxic septic shock (Tigris): a multicentre, open-label, Bayesian, randomised, controlled, phase 3 trial · The Lancet Respiratory Medicine · 2026
• TNF-alpha: Roles in pathogenesis and therapeutics in cancer · Journal of Biological Chemistry · 2026
• Pathogen characteristics are key determinants of distinct host response phenotypes of sepsis · Journal of Clinical Investigation · 2026
• Metabolic control of immunity and inflammation: Mitochondrial dynamics, pharmacological targets, and therapeutic opportunities · Pharmacological Research · 2026
• Sex differences in immune responses to viruses, bacteria and vaccines · Nature Immunology · 2026
• 2′-O-Methyl-guanosine RNA fragments antagonize TLR7 and TLR8 to limit autoimmunity · Nature Immunology · 2026
• Sex-dependent modulation of social distance by lipopolysaccharide-induced inflammation in mice · Translational Psychiatry · 2026
• Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling · JHEP Reports · 2026
• Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts · Journal of Advanced Research · 2026
• Exploring the importance of translational regulation in the inflammatory responses by a genome-wide approach · PubMed · 2026

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