Hernán F. Peñaloza

Inflammation is a multifaceted response involving molecular and cellular components triggered by diverse stimuli, including physical, chemical, and biological factors. The connection between these stimuli and inflammatory cellular responses involves numerous interactions among molecular components, resulting in cell outputs that can either help resolve potential harmful outcomes or amplify them, leading to further complications. Notably, heat shock factor 1 (HSF1), a transcription factor primarily associated with cellular responses to elevated temperatures, has also been reported to play a key role in modulating inflammation. Indeed, growing evidence suggests a close relationship between HSF1 and intracellular signaling pathways that regulate the secretion of inflammatory cytokines, impacting both infectious and non-infectious diseases. Furthermore, chaperone proteins known as heat shock proteins (Hsps), which HSF1 transcriptionally regulates, also play important roles during inflammation by modulating numerous host factors involved in this process. Here, we examine the interplay between HSF1 and Hsps in the context of inflammation caused by infectious and non-infectious diseases. We also discuss the potential benefits of targeting these factors as strategies for reducing the effects of exacerbated or damaging inflammation.

Inflammatory bowel disease (IBD) is a chronic and progressive disorder of the digestive tract, including Crohn’s disease and ulcerative colitis. Over the last decade, IBD has been extensively studied due to its association with dysregulated intestinal microbiota, increased mucosal permeability, and immune imbalance. Despite available pharmacological treatments, there is no definitive cure. Mucosal healing (MH) has emerged as a crucial therapeutic target, as it aims to restore the integrity of inflamed mucosae and is associated with improved clinical outcomes. However, most clinical studies rely primarily on clinical indices rather than direct endoscopic or histologic assessment of MH, and the optimal vitamin D (VD) dosing required to achieve true MH remains unclear. This review aims to examine the diverse functions of VD in modulating pathways relevant to MH within the context of IBD, highlighting its role in immune modulation, intestinal barrier integrity, and gut microbiota composition, and to discuss its potential therapeutic value in IBD management. Relevant experimental, translational, and human clinical studies focusing on VD status, supplementation, and mechanisms related to MH, immune regulation, and intestinal barrier function in IBD were considered. MH involves epithelial restitution, cell proliferation, and differentiation, and its achievement has been associated with reduced symptoms, lower relapse rates, and decreased need for surgical interventions. Beyond its traditional role in bone health, VD plays a critical role in preserving intestinal barrier integrity and regulating immune homeostasis. While biological evidence indicates that VD modulates immune responses, enhances tight junction integrity, and influences gut microbiota composition, clinical data primarily support its role in improving clinical and biochemical disease activity rather than definitively inducing mucosal repair. This review highlights VD as a relevant immunomodulatory and barrier-protective factor with potential complementary value in the clinical management of patients with IBD.

Infectious diseases and autoimmunity are leading causes of mortality worldwide. The lack of vaccines and resistance to current treatments by microbes highlight the importance of developing novel therapeutics. Similarly, treatments for autoimmune diseases are limited and require improved approaches. Identifying relevant proteins involved in host defense and tolerance to self-antigens is key to designing novel therapeutic strategies. Thrombospondin-1 (TSP-1) is a host glycoprotein involved in host defense and inflammation. Here, we analyze how TSP-1 interacts with different ligands involved in immunity. Then, we discuss the roles of TSP-1 in infection and autoimmunity to finally examine the therapeutic potential of TSP-1.

Pseudomonas aeruginosa ( P. aeruginosa ) is a leading cause of hospital- and ventilator-associated pneumonia, driven by virulence factors that damage lung tissue. Neutrophils and monocytes are myeloid immune cells that play key roles in host defense during pulmonary infection against P. aeruginosa ; although if not properly regulated, their inflammatory activity can lead to severe lung injury. Thrombospondin-1 (TSP-1) is a host glycoprotein that regulates neutrophil activation in the lungs during P. aeruginosa infection, protecting the host from mortality. Here, we demonstrate that in addition to regulating the pro-inflammatory phenotype of neutrophils, during P. aeruginosa infection, TSP-1 induces IL-10 in the lung tissue of mice inoculated with this bacterium. Our data show that neutrophils and Ly6C ⁺ monocytes are major sources of lung IL-10 during the first 48 h post-infection, a cytokine that is required for host survival, host defense, and to reduce lung inflammation and injury. Further in vitro studies determined that TSP-1 induces IL-10 production in lipopolysaccharide-stimulated CD11b ⁺ Ly6G ⁺ Ly6C ⁺ cells differentiated from bone marrow precursors through a mechanism dependent on the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Importantly, intratracheal transfer of IL-10 ^+/+ CD11b ⁺ Ly6G ⁺ Ly6C ⁺ cells 1 day before infection to Thbs1 ^−/− mice restored their ability to produce IL-10 in the lungs, improved host defense, and reduced lung inflammation and permeability upon infection. Altogether, our data show that TSP-1 induces IL-10 production in neutrophils and monocytes, enhancing host defense while reducing lung inflammation.

An early event after lung injury is extracellular matrix (ECM) remodeling and the formation of a provisional matrix. While megakaryocytes and platelets (Mgk/plt) play important roles in hemostasis, their impact on the matrix in lung injury is not fully understood. Using lung intravital microscopy, 3D large area scanning with multiphoton confocal hybrid imaging, and label-free quantitative proteomics, the matricellular protein thrombospondin-1 (TSP1) arising from Mgk/plt protects the lung from alveolar injury. Mgk/plt cell-specific Thbs1 knockout (cKO) mice show increased alveolar barrier disruption with exaggerated neutrophil-mediated injury. The cKO mice exhibit striking extracellular matrix re-organization with reduction in basement membrane matrix protein COL6A1 after injury. Moreover, cKO mice increase Mgk numbers to regions of fibrillar collagen deposition and alveolar leak. Our findings indicate Mgk/plt-derived TSP1 represents a key mechanism of matrix stabilization by protecting the basement membrane from neutrophil-mediated proteolytic damage, regulating injury severity and Mgk numbers at the alveolar interface.

Monoclonal antibodies have revolutionized modern medicine due to their target‐specific properties and effectiveness in treating a wide range of diseases, including cancer, autoimmune disorders, infectious diseases, and neurological conditions. Importantly, their large‐scale production for human use requires strict adherence to good manufacturing practice (GMP) standards to ensure quality, safety, and efficacy. This article reviews key aspects of monoclonal antibody production under GMP standards, from cell‐line selection to culture strategies, antibody purification, formulation, and quality control processes. Additionally, we discuss the significance of validation and traceability in production, as well as the implementation of emerging technologies to enhance manufacturing efficiency and safety. Despite progress in bioprocesses and regulatory frameworks, several challenges, such as batch‐to‐batch variability, high production costs, and the need to continuously adapt processes to new regulations, remain to be solved. The integration of innovative approaches with evolving regulations will enable the optimization of monoclonal antibody production and ensure their global accessibility.

Interleukin‐33 (IL‐33) is an IL‐1 family cytokine that activates various immune cells and induces both systemic and localized Th2 responses during infection. An association between IL‐33 and its suppresion of tumorigenicity 2 (ST2) receptor with inflammation during respiratory tract infection has been previously reported. Furthermore, some data suggest that during respiratory infections, IL‐33 may serve as an indicator of disease severity, as high levels of this cytokine have been found in nasopharyngeal swab (NPS) samples of infants with lower respiratory tract disease caused by respiratory syncytial virus (RSV). As viral diagnosis is mostly compartmentalized in NPS, in this report, we aimed at detecting IL‐33 in NPS from patients with respiratory tract infections that were collected in two different transport media (universal transport medium [UTM], and phosphate‐buffered saline [PBS]). IL‐33 levels were evaluated in 230 NPS samples, 121 obtained in PBS, and 109 in UTM. The samples were tested for RSV, metapneumovirus, adenovirus (ADV), influenza, and parainfluenza. In this cohort, higher levels of IL‐33 were detected in virus‐positive samples collected in PBS compared to virus‐negative samples collected in the same transport medium. In addition, RSV‐ and FLU‐positive samples collected in PBS showed higher measured IL‐33 levels than those collected in UTM. No significant differences were found for the other viruses included in this study. These findings highlight the importance of considering sample collection and transport conditions when interpreting IL‐33 measurements in NPS, particularly in future studies evaluating IL‐33 as a potential severity‐associated biomarker during RSV or influenza infection.

The Omicron lineage of SARS-CoV-2 showed a remarkable ability to escape vaccine-induced immunity. In a Phase 2 clinical trial, we investigated whether a th

Annual vaccination is an effective strategy for preventing severe disease caused by seasonal influenza. Quadrivalent influenza vaccines (QIVs) protect against two strains of influenza A and two strains of influenza B, thereby enhancing the host antiviral neutralizing antibody response and inducing CD4⁺ and CD8⁺ T cell responses. Here, we report findings from a randomized, double-blind, active-controlled phase 3 clinical trial (NCT05431725) that includes 334 healthy adults aged 18–64 years and evaluates the humoral and cellular antiviral immune responses induced by two inactivated QIVs, Sinovac-QIV and Vaxigrip-Tetra™. The primary endpoint of the study is the specific antibody responses measured by hemagglutination inhibition (HAI) assays 28 days post-vaccination, while the secondary endpoint is virus-specific T cell responses. Both QIVs elicit significant increases in antibody titers 28 days after vaccination; Sinovac-QIV induces 9–10-fold increases in geometric mean titers, while Vaxigrip-Tetra™ elicits 7–8-fold increases (p < 0.05). Cellular immune responses using ELISPOT and supervised and unsupervised flow cytometry analyses show that both vaccines modulate the frequency of hemagglutinin-specific CD4⁺ and CD8⁺ T cell subsets, inducing distinct T cell response profiles. Although cellular analyses are evaluated in a subgroup of the cohort, the data indicate that both QIVs induce robust humoral and cellular immunity in adults, providing mechanistic insights into vaccine-induced protection.

The T cell response induced by SARS-CoV-2 vaccines is an essential component of immune protection against COVID-19. Multiparametric flow cytometry analysis emerges as a valuable tool for in-depth assessment of T cell phenotype nuances that occur after booster vaccination, such as a fifth dose of an inactivated SARS-CoV-2 vaccine. Figure created with BioRender.com.