Progesterone administration reduces the number of hypertrophic microglia/macrophages and modulates the expression profile of M1/M2 markers and inflammasome components after acute experimental spinal cord injury

CORONEL MF; GONZALEZ SUSANA LAURA; FERREYRA SOL; RAGGIO MC; LABOMBARDA MF

Torino

Congreso; International Meeting -Steroids and Nervous System; 2021

UNIVERSITA DEGLI ESTUDI DI MILANO

Neuroinflammation is a hallmark of central nervous system pathologies, including spinal cordinjury (SCI). In particular, the acute activation of macrophages and resident microglia are critically implicated in the detrimental long-standing consequences of spinal trauma, such as the onset and maintenance of neuropathic pain [5]. Indeed, the fine-tuning of microglia/macrophage polarization fromclassically-activated (M1, inflammatory) towards alternatively-activated (M2,anti-inflammatory) states represents an active research focus of restorativestrategies in a wide range of experimental nervous system trauma, including SCI [1], and may offer a therapeutic opportunity to prevent the risk of developing pain later. We have previously shown that progesterone, a neuroactive steroid, exhibits neuroprotective and pro-myelinating actions in experimental spinal lesions [3, 6] and could stand as a promising repositioning molecule for timely targeting the harmful aspectsof acute inflammation [2, 4], while preserving anti-inflammatory and pro-reparative features. Hence, by using real time RT-PCR and immunohistochemical techniques we evaluate the hypothesis that progesterone could modulate microglia/macrophage morphology and the mRNA expression profile of cytokines, M1/M2 biomarkers and inflammasome components at the dorsal spinalcord level, a critical site for nociceptive processing, in a well-recognizedrat model of spinal hemisection that develops central neuropathic pain. Here weobserved that progesterone administration (16 mg/kg, daily sc injection) withinthe acute phase (1?3 days post-SCI) reduced the injury-induced mRNA expression of several biomarkers of neuroinflammation, including critical inflammasomecomponents NLRP3 and ASC, two related pro-inflammatory cytokines IL-1β andIL-18, ATP-gated P2X7 ion channel and inducible nitric oxide synthase, allsignatures associated with M1 phenotype, while maintaining high levels of  Arginase 1 and CD206, both M2-associated markers,and the anti-inflammatory cytokine TGF-β. Along with these changes,progesterone-treated animals did not change the injury-induced increase in thetotal number of OX-42 microglia/macrophages positive profiles, but exhibited a significantly higher number of ramified cells and a concomitant decrease inhypertrophic/ameboid phenotypes in the dorsal horn as compared toinjured-animals receiving vehicle. Collectively, our results suggest thatprogesterone may avoid a broad suppression of microglia/macrophages, promotinga balance towards anti-inflammatory phenotypes that may underlie the anti-allodynic mechanisms of this steroid. These findings add new evidence to further stimulate the study of neuroactive steroids-based therapies and may open novel translational perspectives for effectively modulating the acuteneuroinflammatory cascade in order to prevent the harmful enduring outcomesafter spinal trauma, such as central pain.Supportedby grants from Consejo Nacional de Investigaciones Científicas y Tecnológicas(CONICET, PIP 112-201501-00266), Agencia Nacional de Promoción Científica yTécnica (PICT 2018-02152)