PNRR-MAD-2022-12376878 - Trained immunity in the inflammatory cascade of chronic inflammatory skin diseases: possible checkpoints and new therapeutic targets

Trained immunity in the inflammatory cascade of chronic inflammatory skin diseases: possible checkpoints and new therapeutic targets

Cup C91J22000490001
Rup  Prof. Egidio Barbi
IRCCS Burlo Garofolo
Via dell’Istria 65/1 – 34137 - Trieste
Finanziamento next generation EU

The role of the innate immune system is crucial in the development of several autoimmune and chronic inflammatory skin diseases, such as psoriasis (PSO) and hidradenitis suppurativa (HS).

Since it has been demonstrated a deep involvement of 'trained immunity' in the pathogenesis of autoinflammatory diseases as rheumatoid arthritis and given its overlapping with psoriatic arthritis (PSA), we hypothesize that trained immunity could be relevant in the pathogenesis of such dermatoses and consider of primary importance to investigate the contribution of trained immunity in chronic inflammatory diseases as PSO, PSA and HS. Considering also the strong skin manifestation of chronic graft-versus-host disease (cGVHD) in post- hematopoietic cell transplantation patients, characterized by the involvement of trained immunity players, we also include cGVHD in the study.

In particular, the study will include adult patients with moderate to severe PSO or affected by severe HS. The study will also include a pediatric population affected by moderate/severe PSO and young patients affected by cGVHD with chronic skin manifestations. Patients blood monocytes and progenitor cells will be screened for the basal trained phenotype, for the response to classical stimuli of TLR and NLR pattern recognition receptors and to a secondary stimulation since trained immunity is known to induce a stronger and broader response to a second stimulation. The analyses will be performed, when available, on primary normal human fibroblasts and keratinocytes conditioned with typical proinflammatory medium, to evaluate their contribution to the trained immunity phenotype at skin level.

On the same models, the immunologic pathways involved in trained phenotype and the main metabolic circuits will be analyzed. Moreover, to identify novel inflammatory and immunometabolic pathways that are under epigenetic regulation, epigenomic profiles will be generated for patients monocytes and keratinocytes for histone marks positively associated with gene expression. Finally, RNA sequencing will be performed to identify specific molecular signatures associated with trained immunity.

Another fundamental point of the research is the selection of new drugs potentially able to target the identified immunometabolic and epigenetic specific molecular signatures, that will be developed using the High Content Screening (HCS) system. Drugs that will result more effective from screening with the HCS system and from proteomic and cytokine profile analysis will be tested on patients¿ monocytes, fibroblasts and keratinocytes to revert the trained immunity phenotype involved in chronic inflammation in a perspective of a personalized medicine approach.

Since the effective compounds selected may have low solubility, poor penetration through the stratum corneum and/or chemical-physical instability, great importance will be done to set nanotechnological systems in order to overcome these problems. The most promising nanostructures will be loaded with selected drugs and tested in 3D in vitro models mimicking the skin structure to verify the potential advantage in terms of bioavailability and effectiveness.

Our study could open new insights on the role of trained immunity in the maintenance of the inflammatory process of the above-mentioned diseases, possibly leading to new personalized therapeutic approaches.
 

Dettagli:

Missione: M6 – Salute;

Componente: M6C2 – Innovazione, ricerca e digitalizzazione del Servizio Sanitario

Investimento: 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN

Amministrazione Titolare: Ministero della Salute

Soggetto Attuatore: Azienda Ospedaliera Universitaria Luigi Vanvitelli (Regione Campania)

Importo finanziato

Avanzamento del progetto

Stato di avanzamento: In corso.