Thèse les Mitochondries Comme Plateforme d'Intégration et de Modulation du Stress Chimique Environnemental dans les Kératinocytes H/F - 75

Établissement : Université Paris-Saclay GS Santé et médicaments
École doctorale : Innovation thérapeutique : du fondamental à l'appliqué
Laboratoire de recherche : Inflammation, Microbiome, Immunosurveillance
Direction de la thèse : Saadia KERDINE-RÖMER ORCID 000000033313952X
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-04-22T23:59:59

La dermatite allergique de contact (DAC) est une pathologie inflammatoire cutanée fréquente, résultant de l'exposition à des molécules chimiques sensibilisantes (CS). Les kératinocytes (KC), cellules majoritaires de l'épiderme, constituent la première ligne de défense face à ces agressions environnementales. Loin d'être de simples cellules structurales, les KC sont immunocompétents et capables de produire, de moduler et d'intégrer des signaux inflammatoires, contribuant ainsi à la régulation de l'immunité cutanée et à la composition du microenvironnement local. Ils jouent donc un rôle déterminant dans l'initiation et l'amplification des réponses immunitaires. L'émergence du concept d'immunométabolisme a profondément renouvelé la compréhension des réponses inflammatoires, en mettant en évidence des reprogrammations métaboliques majeures associées à l'activation immunitaire. Au-delà de leur fonction bioénergétique, les mitochondries apparaissent aujourd'hui comme des plateformes centrales de signalisation, capables de moduler les voies inflammatoires via le contrôle des états métaboliques et la production d'espèces réactives de l'oxygène mitochondriales (mtROS). Cependant, lorsque les mécanismes de contrôle de la qualité mitochondriale sont dépassés, un dysfonctionnement mitochondrial peut survenir. La libération de composants mitochondriaux, tels que les mtROS ou divers métabolites, peut alors agir comme des motifs moléculaires associés aux dommages (mtDAMPs), favorisant l'activation de réponses inflammatoires. Des travaux préliminaires de notre équipe, ainsi que plusieurs études récentes, suggèrent un lien étroit entre le dysfonctionnement mitochondrial, les réarrangements métaboliques et l'acquisition d'un phénotype pro-inflammatoire chez les KC exposés aux CS.
L'objectif principal de ce projet est donc d'identifier les mécanismes par lesquels les mitochondries régulent l'immunité innée des kératinocytes et contribuent au développement de l'inflammation cutanée induite par les CS. Nous analyserons l'impact de ces agents chimiques sur la fonction mitochondriale des KC, en évaluant le métabolisme énergétique, la production de mtROS et la génération de mtDAMPs. Une attention particulière sera portée à l'association entre les altérations mitochondriales observées et les signatures inflammatoires propres à chaque composé testé. Une approche mécanistique permettra de déterminer la contribution respective de ces différents processus à l'acquisition du phénotype inflammatoire. Enfin, le rôle de la réponse mitochondriale aux protéines mal repliées (mtUPR) sera exploré. Ce mécanisme adaptatif, essentiel au maintien de la protéostase mitochondriale, pourrait constituer un déterminant clé de la résilience ou, au contraire, de la vulnérabilité des kératinocytes face au stress chimique.The skin constitutes the primary interface between the body and the external environment and acts as both a physical and immunological barrier against chemical, microbial, and physical insults. Allergic contact dermatitis (ACD) is one of the most prevalent inflammatory skin diseases and results from exposure to low-molecular-weight electrophilic chemicals or metal ions acting as sensitizers. ACD is a type IV delayed hypersensitivity reaction initiated by danger signals perceived by skin-resident cells, leading to activation of innate immunity and the establishment of a pro-inflammatory microenvironment (Scheinman et al., 2021). Although ACD involves complex interactions between antigen-presenting cells, T and B lymphocytes, NK cells, mast cells, endothelial cells, and platelets, keratinocytes (KCs), the most abundant epidermal cell population, are now recognized as active regulators of cutaneous immunity. Beyond their structural role in maintaining barrier integrity, KCs are immunocompetent cells equipped with pattern recognition receptors (TLRs, NLRs, RLRs, CLRs) that enable them to detect pathogen- and damage-associated molecular patterns, cytokines, ultraviolet radiation, and chemical sensitizers. Upon activation, KCs produce cytokines, chemokines, interferons, and growth factors that orchestrate immune cell recruitment and activation (Jiang et al., 2020; Das et al., 2022). Thus, keratinocytes are not passive targets but central integrators of environmental stress and key contributors to innate immune activation in ACD.
Immune activation is tightly linked to metabolic reprogramming. The field of immunometabolism has demonstrated that pro-inflammatory activation is associated with a metabolic shift toward aerobic glycolysis, whereas regulatory phenotypes rely more heavily on oxidative phosphorylation and fatty acid oxidation (Ahl et al., 2020; Soto-Heredero et al., 2020). While such metabolic control mechanisms have been extensively described in classical immune cells and in chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (Cibrian et al., 2020), the metabolic adaptations occurring in keratinocytes upon exposure to chemical sensitizers remain poorly characterized. Preliminary data from our group indicate that cinnamaldehyde alters mitochondrial bioenergetics in keratinocyte cell lines (Vallion et al., 2022). In parallel, other sensitizers, such as DNBS and nickel chloride, have been shown to modulate proteins involved in glucose metabolism, fatty acid pathways, and oxidative phosphorylation in keratinocytes (Menzel et al., 2023) and to be associated with increased production of pro-inflammatory cytokines (IL-1, IL-6, IL-8, TNF-). However, whether these metabolic alterations represent a driving mechanism of inflammation or a secondary consequence of immune activation remains unknown. The causal and mechanistic relationships among mitochondrial dysfunction, metabolic rewiring, and inflammatory signaling in keratinocytes during ACD remain unclear.
Mitochondria are central regulators of cellular metabolism by producing ATP via the tricarboxylic acid cycle and the mitochondrial respiratory chain. Growing evidence indicates that mitochondrial dysfunction is a major hallmark of environmental insults (Duarte-Hospital et al., 2021). Beyond bioenergetics, mitochondria also control calcium homeostasis, reactive oxygen species (ROS) production, apoptosis, and innate immune signaling. Increasing evidence indicates that mitochondria are key immunological hubs (Mills et al., 2017; Marques et al., 2024). Mitochondrial metabolites, mtROS, and mitochondrial DNA contribute to inflammasome activation and modulation of Toll-like receptor signaling (Jiao et al., 2023; Olona et al., 2022). Thus, when mitochondrial quality control mechanisms are overwhelmed by environmental triggers, mitochondrial dysfunction may result in impaired oxidative phosphorylation, increased ROS production, proteotoxic stress, and release of mitochondrial DAMPs such as ATP and mtDNA, thereby amplifying inflammatory responses (West, 2017). Although mitochondrial dysfunction has been implicated in inflammatory skin diseases and immune-mediated disorders (Hanaford and Johnson, 2022; Leman et al., 2022; Minzaghi et al., 2023), its specific contribution to chemically induced inflammation in ACD remains largely unexplored. In particular, the role of mitochondrial stress adaptation pathways in keratinocytes exposed to sensitizers is unknown. While contact sensitizers have been shown to activate the endoplasmic reticulum unfolded protein response (UPR) (Esser et al., 2023), their impact on the mitochondrial unfolded protein response (mtUPR) remains uninvestigated. The mtUPR is a conserved adaptive pathway that restores mitochondrial proteostasis by activating nuclear-driven transcriptional programs in response to mitochondrial dysfunction (Anderson and Haynes, 2020; Sutandy et al., 2023).
Altogether, these observations highlight a major unresolved question: do mitochondria function as central integrators of chemical stress in keratinocytes, thereby driving metabolic reprogramming and shaping innate immune activation in ACD? Addressing this question will improve our understanding of the early molecular events linking chemical exposure to inflammatory skin responses and may reveal new mechanistic targets for modulating cutaneous inflammation.

This project will clarify whether mitochondria function as central integrators of chemical stress in keratinocytes and define their contribution to early inflammatory events in allergic contact dermatitis. By linking mitochondrial dysfunction, metabolic reprogramming, and innate immune activation, this work may reveal novel mechanistic targets for modulating cutaneous inflammation.

Chemical sensitizers with distinct reactivities and sensitizing potentials will be selected to capture different modes of protein interaction. Hydroxycitronellal (low sensitizing potential; Schiff base formation) will be compared with highly potent sensitizers, such as methylisothiazolinone (MIT) and 1-chloro-2,4-dinitrobenzene (DNCB), which interact with proteins via ring-opening or Michael-addition mechanisms.
Experiments will be conducted in human primary keratinocytes to ensure physiological relevance. Mechanistic investigations will then be performed in KERTr and N/TERT-1 keratinocyte cell lines, which express TLRs and exhibit TLR responsiveness comparable to primary keratinocytes (Miller, 2008; Olaru and Jensen, 2010). This strategy will allow validation of key findings in primary cells while enabling deeper mechanistic exploration in stable and reproducible models.
Attention will be paid to the chronology of events following chemical exposure to distinguish early mitochondrial alterations from downstream inflammatory responses.

WP1 - Characterization of mitochondrial dysfunction and metabolic reprogramming

WP2 - Assessment of inflammatory activation and mitochondrial DAMP release

WP3 - Mechanistic dissection of mitochondria-inflammation crosstalk