Open research questions in Immune Response and Inflammation

What the literature leaves open

• Direct interactions between TLRs and advanced formulations or semi-synthetic derivatives remain insufficiently documented, - Clinical data in autoimmune conditions are limited, - The potential toxicity of coumarin, especially in Cassia cinnamon, is a concern

  Cinnamon and Derivatives as Modulators of Toll-like Receptors · 2026 · DOI

• Investigation of direct interactions between TLRs and advanced formulations or semi-synthetic derivatives, - Clinical trials to confirm the efficacy of cinnamon-derived compounds in TLR-mediated diseases, - Studies on the potential toxicity of coumarin and its effects on human health

  Cinnamon and Derivatives as Modulators of Toll-like Receptors · 2026 · DOI

• The study was conducted in mice, - The study used a limited number of bacterial challenges, - The study did not investigate the long-term effects of ASA administration

  Evaluating the in vivo effects of Aspirin on vaginal inflammation and barrier function · 2026 · DOI

• Investigate the long-term effects of ASA administration on vaginal homeostasis, - Examine the effects of ASA administration on other types of vaginal infections, - Study the mechanisms by which ASA modulates immunologic and metabolic pathways

  Evaluating the in vivo effects of Aspirin on vaginal inflammation and barrier function · 2026 · DOI

• Although type I IFNs are key drivers of autoantibody production in systemic lupus erythematosus (SLE), their role in bacterial biofilm-induced autoimmunity remains unclear.

  Contribution of local Salmonella infection to autoreactivity: divergent roles of type I interferons in colonization and autoantibody production · 2026 · DOI

• TGFβ is an important regulator of AM differentiation and maintenance, but how TGFβ directly modulates the innate immune responses of AMs remains unclear.

  TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation · 2026 · DOI

• However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear.

  Structural basis for TIR domain–mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM · 2025 · DOI

• However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood.

  Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections · 2025 · DOI

• However, the dynamic changes of the immune system during the disease progression in the brain remains unclear.

  A single-cell atlas of mouse central nervous system immune cells reveals unique infection-stage immune signatures during the progression of meningitis caused by Streptococcus suis · 2025 · DOI

• However, the cell-type-specific and organ-specific expression dynamics of these receptors during sepsis remain poorly characterized.

  Decoding IL-1 receptor 1 and 2 expression profiles across organs in sepsis · 2025 · DOI

• Th9 cells interact with TL1A, produce IL-9, and participate in IBD development; however, their specific role in IBD remain unclear.

  Restoring Balance: RIPK1 inhibitor counteracts TL1A-induced T cell responses 2199 · 2025 · DOI

• Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear.

  Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling 3024 · 2025 · DOI

• This review explores the reported mechanisms regulating IL-6 induction in response to IAV and its innate immune role in IAV pathogenesis, highlighting existing research gaps in understanding IAV-induced IL-6 production and its impact on immune modulation.

  Innate immune role of IL-6 in influenza a virus pathogenesis · 2025 · DOI

• However, the precise pathways responsible for excessive IL-6 production and its dysregulation during IAV infection is not fully understood.

  Innate immune role of IL-6 in influenza a virus pathogenesis · 2025 · DOI

• The role of Parthenolide (PTL) in regulating SIC by protecting VECs remains unclear.

  Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway · 2025 · DOI

• Since the dynamics of immune cells, cytokines and novel markers such as circulating extracellular vesicles (EVs) remain incompletely elucidated, we aimed to provide a comprehensive multiparametric characterization of this severe response, to identify potential prognostic and therapeutic targets.

  Immune cell dynamics, cytokines, and extracellular vesicles in systemic inflammatory response syndrome (SIRS): a multiparametric analysis · 2025 · DOI

• Historically, research has primarily focused on the reactogenicity of mRNA cargo, leaving the role of LNPs understudied in this context.

  Lipid Nanoparticles Elicit Reactogenicity and Sickness Behavior in Mice Via Toll-Like Receptor 4 and Myeloid Differentiation Protein 88 Axis · 2024 · DOI

• The physiological roles of AHR expressed in the alveolar epithelium remain unclear.

  Aryl Hydrocarbon Receptor Activation in Pulmonary Alveolar Epithelial Cells Limits Inflammation and Preserves Lung Epithelial Cell Integrity · 2024 · DOI

• Further investigation into the underlying molecular mechanisms of costimulation revealed that TCRγδ-mediated activation of NFAT and JNK is required for type I IFN to promote IFN-γ expression in a STAT4-dependent manner.

  Type I IFN Induces TCR-dependent and -independent Antimicrobial Responses in γδ Intraepithelial Lymphocytes · 2024 · DOI

• The production of type I IFN is a central component of an antiviral immune response, yet how these proinflammatory cytokines contribute to γδ IEL effector function remains unclear.

  Type I IFN Induces TCR-dependent and -independent Antimicrobial Responses in γδ Intraepithelial Lymphocytes · 2024 · DOI

• Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10.

  TLR10 (CD290) Is a Regulator of Immune Responses in Human Plasmacytoid Dendritic Cells · 2024 · DOI

• However, the dynamics of specific microbiota components in intestinal tissues at different sepsis stages remain unclear.

  Dynamic changes in the migratory microbial components of colon tissue during different periods of sepsis in an LPS-induced rat model · 2024 · DOI

• However, the reciprocal interaction between intestinal immune cells and intestinal flora in the progression of ET-infection remains unclear.

  Correlation of caecal microbiome endotoxins genes and intestinal immune cells in Eimeria tenella infection based on bioinformatics · 2024 · DOI

• Nevertheless, the exact role of A20 in the BEECs in response to inflammatory response is not fully understood.

  A20 Alleviates the Inflammatory Response in Bovine Endometrial Epithelial Cells by Promoting Autophagy · 2024 · DOI

• Establishing cross-scale research methods is necessary to understand how phase-separated TLR signalosomes selectively recruit or exclude specific RBP-RNA complexes.

  Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights · 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

• Immune-microbiome coordination defines interferon setpoints in healthy humans · Cell · 2026
• Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights · Immunity & Inflammation · 2026
• Shared Genomic Architecture Between Schizophrenia and Multiple Sclerosis Identifies an Un-Drugged HCAR1 Neuroimmune Checkpoint · bioRxiv · 2026
• TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation · The Journal of Immunology · 2026
• Solithromycin mitigates Prevotella intermedia–induced methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia by enhancing alveolar macrophage function · Frontiers in Cellular and Infection Microbiology · 2026
• Probing Immune Signatures of Conjugated Pattern Recognition Receptor Ligands Identifies Chimeras with Potent Adjuvant and Antitumor Activities · Journal of Medicinal Chemistry · 2026
• Preclinical development of SL-325, a novel high-affinity DR3-blocking antibody for durable inhibition of the DR3/TL1A axis in inflammatory bowel disease · Inflammatory Bowel Diseases · 2026
• Engineering nanoparticle surface chemistry for antigen-presenting cell targeting improves specificity and safety of TLR3 agonist cancer immunotherapy · bioRxiv · 2026
• Myeloid cell reprogramming drives enhanced defense against Streptococcus pneumoniae lung infection following exposure to commensal Prevotella · bioRxiv · 2026
• Cell death mechanisms in sepsis-associated adaptive immune dysfunction · Journal of Critical Care · 2026

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