Laurent Boyer

Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms them towards a pro-inflammatory phenotype. Our findings position the cathepsin B-caspase-8 axis as an original critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma characterized by poor clinical outcomes following conventional CHOP-based chemotherapy and the lack of effective disease-specific therapeutic options. The disease finds its origin in CD4 follicular helper T (Tfh) cells and is driven by recurrent genetic alterations, including mutations in TET2, RHOA, DNMT3A, and IDH2. Despite the rarity of AITL, preclinical models have been fundamental in elucidating disease pathogenesis, identifying key molecular vulnerabilities and providing platforms for the evaluation of novel therapeutic strategies. These studies have highlighted multiple targetable pathways, including aberrant mTOR, T-cell receptor and NF-κB signaling. Additionally, widespread epigenetic alterations in the neoplastic T-cells were uncovered due to mutations in epigenetic modifiers in AITL. More recently, metabolic reprogramming has emerged as an additional therapeutic vulnerability, revealing a strong dependence of AITL cells on mitochondrial respiration and lipid metabolism, particularly the choline metabolic pathway. Advances in the understanding of AITL biology have also accelerated the development of immunotherapeutic strategies. Monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown encouraging preclinical and early clinical activity. Of note, the first preclinical results on an in vivo CAR-T-cell approach for AITL are reported. Here we provide a broad overview of AITL, discussing its biological features, pathogenesis, preclinical models, current treatment landscape, and recent advances in therapeutic approaches.

Adaptive immune memory generated by bacterial toxin vaccination is well established, but whether bacterial toxins can also induce innate immune memory, or trained immunity (TI), remains unclear. Here, we show that bacterial toxins elicit TI through NLRP3 inflammasome activation both in vitro and in vivo in mice, and that this response is conserved in primary human macrophages. Stimulation with the CNF1 toxin induced an epigenetic remodeling, defining a TI-associated transcriptional signature. A targeted RNAi screen identified Bcl2a1 as a required mediator of TI, and epistasis analyses demonstrated that IL-1 signaling is essential for TI induction in macrophages. In our mouse sepsis model, toxin-induced TI enhanced host resistance and improved survival. These findings establish toxin-driven inflammasome activation as trigger of transient TI and demonstrate that this response enhance resistance during experimental bacterial sepsis.

The activation of pattern recognition receptors (PRRs) orchestrates inflammation and regulates adaptive immunity. To test whether tuning inflammation through PRR stimulation enhanced the efficacy of mRNA vaccines, we combined an mRNA-based vaccine generated against the ancestral spike protein of SARS-CoV-2 with mannadjuvant, a formulation of fungal mannan and aluminum hydroxide targeting the PRR dectin-2. In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting. Mechanistically, prolonged type I interferon (IFN) production and potentiated interleukin-1 (IL-1) signaling locally within the draining lymph node in mice or in human cells were necessary and sufficient to exert the effect of mannadjuvant. Our data indicate that antifungal PRRs can be harnessed to create more potent and durable mRNA-based vaccines.

A new bicyclic polyketide, amesilide (1), along with the previously reported metabolites, chamisides A (2), B (3), and E (4), chaetoconvosins B (5) and C (6), and chaetochromins A (7) and B (8), were isolated from the marine fungus Amesia nigricolor MUT6601. The structures of the compounds were determined by extensive spectrometric (HRMS) and spectroscopic (1D and 2D NMR) analyses, as well as specific rotation. Absolute configurations of the stereogenic centers of amesilide (1) were determined by a comparison of its experimental circular dichroism (CD) spectrum with its time-dependent density functional theory (TD-DFT) electronic circular dichroism (ECD) spectra. Among them, chaetochromins A (7) and B (8) showed strong antibacterial activity against Staphylococcus aureus S25 (MBC values of 12.50 µM and MIC values of 6.25 µM) and a moderate cytotoxicity against monocytes (THP-1) and peripheral blood cells (PBMC) (IC₅₀ values of 33.65–40.01 µM).

Vibrio parahaemolyticus is the leading cause of seafood-borne gastroenteritis. While its interaction with edible marine animals is well known, its impact on non-edible hosts remains under-explored. Using the sea anemone Exaiptasia pallida, we investigated Vibrio parahaemolyticus pathogenicity and the role of the Type III Secretion System (T3SS). In vivo infections with a 107 CFU/mL inoculum of V. parahaemolyticus induced a 50% mortality rate after 7 days (LC50). Using isogenic mutant strains of V. parahaemolyticus with impaired key regulatory components of T3SS, impT3SS1 (CAB2), and impT3SS2 (CAB3), we demonstrated that disruption of T3SS1 significantly reduced anemone mortality. Next, we observed a time-dependent downregulation of T3SS1 effectors (VPA0450, VopQ, VopS) after 3 h and 6 h in the presence of the sea anemone, contrasting with the T3SS2-dependent VopC increased expression after 6 h. Further results support the capacity of V. parahaemolyticus to sense host-derived chemical cues and adjust its virulence strategies accordingly. Collectively, our findings broaden the understanding of V. parahaemolyticus O3:K6 as a pathogen for cnidarians and provide evidence of a major role for the T3SS1 effectors in this emerging model of host–pathogen interactions.

Médecine/sciences (M/S), revue internationale dans le domaine de la recherche biologique, médicale et en santé

Objetivo: o objetivo deste estudo foi analisar perfis latentes de estigma internalizado e as covariáveis que preveem variações em seus níveis, considerando antecedentes como origem étnica, sexo e determinadas características clínicas relevantes, como ajuste pré-mórbido, duração da psicose não tratada e sintomas. Método: a Análise de Classe Latente (ACL) foi utilizada para desenhar uma solução com três perfis de estigma internalizado em uma amostra composta por 227 pacientes diagnosticados com esquizofrenia atendidos em centros públicos de saúde mental na cidade de Arica, Chile. Resultados: os resultados evidenciaram que o ajuste pré-mórbido é um preditor significativo de pertencimento a uma classe para perfis de estigma latente. Ao analisar as características sociodemográficas e, contrariamente à nossa hipótese, a origem étnica não foi um preditor relevante dos perfis de estigma internalizado. Conclusão: o modelo de classificações latentes é adequado para avaliar perfis de estigma a fim de projetar intervenções futuras com focos específicos e populações de risco.

Objective: this study aimed at analyzing the internalized stigma latent profiles and the covariates that predict variations in their levels considering antecedent variables such as ethnicity, gender and some relevant clinical characteristics like premorbid adjustment, Duration of Untreated Psychosis and symptoms. Method: Latent Class Analysis (LCA) was used to devise a solution with three internalized stigma profiles in a sample comprised by 227 patients diagnosed with schizophrenia from the Public Mental Health Centers of the city of Arica, Chile. Results: the results showed that premorbid adjustment is a significant predictor of class belonging for the latent stigma profiles. When analyzing the sociodemographic characteristics and contrary to what was hypothesized, ethnicity was not a relevant predictor of internalized stigma profiles. Conclusion: the latent classification model is suitable for assessing stigma profiles in order to target future interventions in specific foci and at-risk populations.

Objetivo: el propósito de este estudio fue analizar los perfiles latentes de estigma internalizado y las covariables que predicen variaciones en sus niveles considerando antecedentes como origen étnico, sexo y ciertas características clínicas relevantes como ajuste premórbido, Duración de psicosis no tratada y síntomas. Método: se utilizó Análisis de Clases Latentes (ACL) para diseñar una solución con tres perfiles de estigma internalizado en una muestra compuesta por 227 pacientes con diagnóstico de esquizofrenia atendidos en los centros públicos de Salud mental de la ciudad de Arica, Chile. Resultados: los resultados demostraron que el ajuste premórbido es un predictor significativo de pertenencia a una clase para los perfiles de estigma latente. Al analizar las características sociodemográficas y contrariamente a nuestra hipótesis, el origen étnico no fue un predictor relevante de perfiles de estigma internalizado. Conclusión: el modelo de clasificaciones latentes es apto para evaluar perfiles de estigma con el fin de diseñar futuras intervenciones en focos y poblaciones en riesgo específicos.