Sepsis remains a common cause of death in intensive care units, accounting for approximately 20% of total deaths worldwide. Its pathogenesis is partly attributable to dysregulated inflammatory responses to bacterial endotoxins (such as lipopolysaccharide, LPS), which stimulate innate immune cells to sequentially release early cytokines (such as tumor necrosis factor (TNF) and interferons (IFNs)) and late mediators (such as high-mobility group box 1, HMGB1). Despite difficulties in translating mechanistic insights into effective therapies, an improved understanding of the complex mechanisms underlying the pathogenesis of sepsis is still urgently needed. Here, we review recent progress in elucidating the intricate mechanisms underlying the regulation of HMGB1 release and action, and propose a few potential therapeutic candidates for future clinical investigations.

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potential sepsis therapy. Here, we report that systemic screening of a NatProduct Collection of 800 natural products led to the identification of a lipophilic sterol, lanosterol (LAN), as a selective inhibitor of pCTS-L-induced production of cytokines [e.g., Tumor Necrosis Factor (TNF) and Interleukin-6 (IL-6)] and chemokines [e.g., Monocyte Chemoattractant Protein-1 (MCP-1) and Epithelial Neutrophil-Activating Peptide (ENA-78)] in innate immune cells. To improve its bioavailability, we generated LAN-carrying liposome nanoparticles and found that these LAN-containing liposomes (LAN-L) similarly inhibited pCTS-L-induced production of several chemokines [e.g., MCP-1, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) and Macrophage Inflammatory Protein-2 (MIP-2)] in human blood mononuclear cells (PBMCs). In vivo, these LAN-carrying liposomes effectively rescued mice from lethal sepsis even when the first dose was given at 24 h post the onset of this disease. This protection was associated with a significant attenuation of sepsis-induced tissue injury and systemic accumulation of serval surrogate biomarkers [e.g., IL-6, Keratinocyte-derived Chemokine (KC), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)]. These findings support an exciting possibility to develop liposome nanoparticles carrying anti-inflammatory sterols as potential therapies for human sepsis and other inflammatory diseases.

Background: 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. Methods: By mapping mAb9’s epitope to P2 (residues 55–70), a region crucial for TN’s protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. We then employed animal models of sepsis (cecal ligation and puncture) and arthritis (collagen antibody-induced arthritis) to evaluate the therapeutic effects of P2, P2-1, and a procathepsin L (pCTS-L)-neutralizing antibody by assessing septic survival, arthritis severity, pain sensitivity, and joint tissue histology. In parallel, we utilized a surface plasmon resonance (SPR) assay and computational modeling to examine the P2-1/high mobility group box 1 (HMGB1) interaction. Finally, we elucidate the effect of P2-1 on the HMGB1-induced release of pCTS-L and other cytokines and chemokines using primary human peripheral blood mononuclear cells (PBMCs). Results: P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in an RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to HMGB1 and selectively suppressed HMGB1-induced cathepsin L ( Ctsl ) mRNA upregulation and 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 antiarthritic effects, reducing joint inflammation, pain, and structural damage. Conclusions: Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from harmful antibody action into targeted therapeutics for the HMGB1-pCTS-L axis. This approach not only delivers P2-1 as a potent therapy but also establishes pCTS-L as a crucial mediator in inflammatory diseases such as 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.