Haichao Wang

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5 ^hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT–mTOR–HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5 ^hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5 ^hi monocytes, highlighting CCR5 ^hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.

Dysregulated inflammation, characterized by the uncontrolled release of inflammatory mediators, is central to the pathogenesis of numerous inflammatory diseases, including acute sepsis and chronic rheumatoid arthritis (RA). Despite therapeutic advances in RA, limitations of current anti-inflammatory treatments—such as broad immunosuppression and partial efficacy—highlight an urgent need for novel interventions. This review critically examines the pathogenic roles of High Mobility Group Box 1 (HMGB1) and procathepsin-L (pCTS-L) in dysregulated inflammation, mediated by their interactions with Toll-like receptor 4 (TLR4) and the Receptor for Advanced Glycation End Products (RAGE). Crucially, we highlight the newly established HMGB1-pCTS-L axis, in which HMGB1 directly upregulates pCTS-L expression and release. This axis initiates a delayed yet sustained inflammatory loop, which may predominantly activate the more enduring non-canonical NF-κB pathway. Furthermore, we explore the intricate role of tetranectin (TN), an endogenous HMGB1-binding protein, which inhibits HMGB1 release but paradoxically facilitates HMGB1-induced pyroptosis. Leveraging this complexity, we introduce the TN-derived P2–1 peptide as a highly specific inhibitor of the HMGB1-pCTS-L axis. This peptide binds HMGB1 to prevent its RAGE engagement and subsequent macrophage pyroptosis, without broadly suppressing initial inflammatory cascades. It also specifically inhibits HMGB1-induced pCTS-L expression and release, ameliorating both sepsis and RA even with delayed treatment. Its “disease-triggered” mechanism, selectively targeting extracellular HMGB1 only at pathological sites, promises enhanced safety and precision. This review positions the HMGB1-pCTS-L axis as a critical and therapeutically tractable pathway, with HMGB1- and pCTS-L-inhibiting antibodies and mimetic peptides representing promising next-generation interventions for a spectrum of inflammatory diseases.

High Mobility Group Box 1 (HMGB1) and Procathepsin L (pCTS-L) are crucial inflammatory mediators, yet their immunomodulating properties in human immune cells have not been systematically compared. This study employed RNA-sequencing to comparatively analyze their transcriptional effects on primary human peripheral blood mononuclear cells (PBMCs). Our findings demonstrate that while both mediators elicited significant transcriptional changes indicative of robust inflammatory responses, HMGB1 consistently induced a more extensive and diversified inflammatory program. Specifically, at a lower concentration of 0.5 µg/ml, HMGB1 triggered nearly four times more differentially expressed genes (DEGs) than pCTS-L (2.0 µg/ml). Despite this quantitative difference, an overlap of 412 DEGs (272 upregulated, 140 downregulated) revealed shared core inflammatory pathways, including the extensive upregulation of pro-inflammatory cytokines (e.g., IL1A, IL1B, and IL6), chemokines (e.g., CCL2 and CXCL1), and S100 proteins (e.g., S100A8, S100A9, and S100A12). Both mediators also converged on activating the non-canonical NF-κB pathway, evidenced by NFKB2 and RELB upregulation, suggesting a common underlying regulatory mechanism. Notably, HMGB1 uniquely upregulated CASP4 and CASP5—key components of the non-canonical inflammasome pathway—and a broader spectrum of cytokines and chemokines (e.g., IL23A, CXCL5). These findings delineate the distinct yet overlapping roles of HMGB1 and pCTS-L in orchestrating immune responses, offering a foundation for targeted therapeutic development for inflammatory diseases.

Several contributions highlight the critical role of endogenous molecular entities in orchestrating cellular communication and shaping the innate immune response. Li et al. (1) reviewed Connexin 43 and Pannexin 1 hemichannels in macrophages, revealing how bacterial lipopolysaccharide (LPS) and serum amyloid A (SAA) upregulate these channels, leading to ATP efflux. This efflux intensifies inflammasome activation, pyroptosis, and the release of pathogenic damage-associated molecular patterns (DAMPs) like high mobility group box 1 (HMGB1), thereby fueling the inflammatory cascade (1). Crucially, the authors demonstrate that mimetic peptides targeting these hemichannels can modulate their activity and impact sepsis-induced lethality, positioning them as significant therapeutic targets (1).Expanding on intercellular communication, You et al. (2) reviewed the pathogenic and therapeutic roles of extracellular vesicles (EVs) in sepsis. EVs, released by both host cells and bacteria, act as vital paracrine components, delivering bioactive materials that can either promote inflammatory responses or serve as tools for therapeutic cargo delivery. This dual role underscores their intricate involvement in both disease progression and tissue repair, suggesting engineered EVs as a novel strategy for diagnosis and targeted intervention (2). This concept is further elaborated by Jiao et al. (3), who focused on tubular epithelial cell (TEC)-derived EVs carrying SAA1. This study uncovers a novel mechanism where these EVs exacerbate sepsis-associated acute kidney injury (SA-AKI) by promoting neutrophil extracellular trap (NET) formation via the TLR4/p38 MAPK pathway (3). Importantly, targeting EV secretion or SAA1 within TECs alleviates both renal and remote lung injury, indicating kidney-lung crosstalk and highlighting TEC-EVs/SAA1 as a potential prognostic index for SA-AKI (3).The versatile protein SAA emerges as a recurrent endogenous regulator across the topic. Mohanty et al. delved into the specific roles of SAA proteins in sterile and infectious diseases, demonstrating their dual functionality (4). SAA amplifies cytokine and chemokine responses during sterile inflammation (where SAA-deficient mice showed better survival) but is essential for bacterial clearance in infectious conditions (where SAA-deficient mice were more susceptible) (4). This intricate balance is mediated via NF-κB signaling, highlighting SAA as a key modulator whose context-dependent actions are critical. The explicit link between SAA and hemichannels (1), and SAA1 carried by TEC-EVs (3), illustrates the complex interplay and functional convergence of these endogenous mediators.The heterogeneity of immune cell responses and their impact on patient outcomes is a central theme. Chen et al. identified a specific subset of CD10-CD121b + neutrophils in septic shock patients that correlated with severity and predicted immunosuppression (5). In these immunosuppressive neutrophils, CD121b blockade led to increased proinflammatory cytokine production. This identifies CD121b as both a predictive indicator and a therapeutic target, particularly as its expression is amenable to down-regulation by all-trans retinoic acid (ATRA) (5).In the context of specific organ injury, Shen et al. reviewed the TREM2 signaling pathway in sepsis-induced acute lung injury (ALI) (6). TREM2, expressed predominantly on myeloid cells, plays a pivotal role in modulating inflammation. Understanding its functions and mechanisms in both physiological and septic lung injury scenarios, along with evaluating TREM2-targeted therapies, is crucial for addressing this severe septic complication (6). Complementing this, Wang et al. focused on lymphocyte subsets as predictors for SA-AKI (7). This study meticulously identified significant alterations in peripheral blood lymphocyte subsets -including various T cell activation/exhaustion markers and myeloid-derived suppressor cells (MDSCs) -that predicted the incidence and severity of SA-AKI (7). The developed predictive model, incorporating these immunological parameters with clinical data, offers a robust tool for early warning and clinical decision-making.The search for precise diagnostic tools is also addressed. Herminghaus et al. investigated the diagnostic utility of IL-18 plasma levels in distinguishing abdominal from non-abdominal sepsis (8). While several inflammatory cytokines were elevated in both sepsis types, IL-18 showed moderate predictive accuracy, particularly for identifying non-abdominal sepsis when its level was below a certain threshold (8). It suggests IL-18 as a useful additional biomarker, highlighting the importance of understanding specific inflammatory signatures based on infection source.Beyond direct immune cell interactions, systemic physiological changes significantly impact innate immunity. The comprehensive analysis of metabolism-related genes (MRGs) in sepsis by Zheng et al. revealed critical metabolic-immune heterogeneity (9). By stratifying patients based on MRGs, this multi-omics study identified a high metabolic risk group characterized by a neutrophil-dominant and lymphocyte-suppressed immune landscape. Glycogenin-1 (GYG1) emerged as a key hub gene, highly expressed in monocytes and neutrophils, and its knockdown significantly improved survival in a murine sepsis model (9). This positions GYG1 as a metabolic driver of innate immune hyperactivation and a promising therapeutic target.The often-overlooked neuro-immune axis receives attention from the review paper by Wang et al. (10), which highlights dopamine as an endogenous regulator of innate immunity in sepsis.Traditionally known for its role in the central nervous system, dopamine is shown to significantly influence the immune response, specifically regulating aconitate decarboxylase 1 (ACOD1) (10). This mini-review underscores the critical, yet under-explored, interplay between the nervous and immune systems in sepsis. Furthermore,...

Sepsis and rheumatoid arthritis (RA) are distinct yet mechanistically related conditions commonly driven by dysregulated inflammatory responses. Here, we explored the counterintuitive hypothesis that an epitope from a deleterious anti-tetranectin (TN) antibody (mAb9) could hold unforeseen therapeutic potential. By mapping mAb9's epitope to P2 (residue 55–70), a region crucial for TN's protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in a RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to high mobility group box 1 (HMGB1) and selectively suppressed HMGB1-induced Ctsl mRNA up-regulation and procathepsin L (pCTS-L) secretion from human immune cells, crucially without perturbing other HMGB1-induced cytokines and chemokines. We further validated pCTS-L as a therapeutic target by demonstrating that a neutralizing antibody conferred potent anti-arthritic effects, reducing joint inflammation, pain, and structural damage. Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from paradoxical antibody action into targeted therapeutics for the HMGB1-pCTS-L axis, not only delivering P2-1 as a potent therapy but also establishing pCTS-L as crucial mediator of inflammatory diseases like sepsis and RA.

Human dermcidin (DCD) is synthesized as a 110-amino acid precursor (pre-dermcidin, pre-DCD) containing a 19-residue leader signal sequence, which is removed to produce a leader-less pro-domain-containing peptide termed as pro-dermcidin, pro-DCD. Pro-DCD can be secreted by human eccrine sweat glands and then cleaved into antimicrobial peptides, such as dermcidin (DCD). Emerging evidence suggests that pro-DCD has broader physiological roles beyond antimicrobial defense, potentially serving as a therapeutic agent for inflammatory diseases like sepsis. In this review, we summarize recent evidence supporting pro-DCD as a regulator of innate immunity in sepsis.

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, presents a major clinical challenge. While the complex interplay of inflammatory mediators and immune cells during sepsis is increasingly understood, the role of neurotransmitters, particularly dopamine, in modulating the innate immune response is emerging as a crucial area of investigation. Dopamine, traditionally recognized for its role in the central nervous system, acts as an endogenous regulator of innate immunity, significantly influencing the course and outcome of sepsis. In this mini-review, we highlight our recent finding of dopamine’s critical role in regulating aconitate decarboxylase 1 (ACOD1) in sepsis.

A 110-amino acid precursor of dermcidin (pre-dermcidin, pre-DCD) with a 19-residue N-terminal leader signal sequence can be secreted by human eccrine sweat glands as a leader-less pro-domain-containing peptide (pro-DCD), which is enzymatically cleaved to generate C-terminal anti-microbial peptides (dermcidin-1, DCD-1) capable of killing various bacteria. Previously, it was unknown whether pro-DCD could be pharmacologically developed as potential therapeutics for lethal sepsis. Here, we demonstrated that pharmacological suppression of pro-DCD with polyclonal antibodies worsened sepsis-induced inflammation and liver injury, whereas supplementation of pro-DCD or its PEGylation derivatives significantly protected against sepsis, even when given 2–24 h after disease onset. These protective effects were associated with a significant reduction in circulating levels of surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF), Interleukin-6 (IL-6), keratinocytes-derived chemokine (KC), Monocyte Chemoattractant Protein 1 (MCP-1), Macrophage Inflammatory Protein-2 (MIP-2), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)], tissue injury, and blood bacterial counts. Although pro-DCD or its PEGylation derivatives failed to directly kill bacteria across a wide range of concentrations, they were able to activate microtubule-associated protein 1A/1B-light chain 3 (LC3), a marker of autophagy and phagosome maturation in LC3-associated bacterial phagocytosis. Our findings suggest that pro-DCD-derived agents hold promise as potential therapies for clinical sepsis.

Pathogen-induced septic death presents a substantial public health challenge, with its neuroimmune mechanisms largely unexplored. Our study investigates neurotransmitter modulation of ACOD1 expression, a regulator of immunometabolism activated by bacterial lipopolysaccharide (LPS). Screening neurotransmitters identifies dopamine as a potent inhibitor of LPS-induced ACOD1 expression in innate immune cells. Mechanistically, DRD2 forms a complex with TLR4, initiating MAPK3-dependent CREB1 phosphorylation and subsequent ACOD1 transcription. Conversely, dopamine disrupts TLR4-MYD88 interaction via DRD2 without affecting the formation of the LPS-induced TLR4-MD2-CD14 complex. Enhanced ACOD1 expression induces CD274/PD-L1 production independently of itaconate, precipitating inflammation-associated immunosuppression in sepsis. Delayed administration of pramipexole, a dopamine agonist, mitigates lethality in bacterial sepsis mouse models. Conversely, the dopamine antagonist aripiprazole exacerbates sepsis mortality. Dysregulation of the dopamine-ACOD1 axis correlates with sepsis severity in patients, indicating a potential therapeutic target for modulating this neuroimmune pathway.