Biology subjects

Davoli-Ferreira, M.

Publications and source records attributed to Davoli-Ferreira, M..

4 recordsLinked to original sources

bioRxiv2024

T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota.

The gut microbiota and immune system maintain intestinal homeostasis and regulate gut physiology in concert with the enteric nervous system (ENS). However, the underlying mechanisms remain incompletely understood. Using wildtype and T-cell deficient germ-free mice colonized with segmented filamentous bacteria (SFB) or specific pathogen-free (SPF) microbiota, we studied immune regulation of the ENS and intestinal motility. Colonization markedly increased Th17 cells and Treg expressing ROR{gamma}+T cells in both the ileum and colon of wildtype mice. T cells were necessary for the normalization of intestinal motility after colonization by SPF microbiota, and for SFB to restore neuronal density in the ENS of the ileum of germ-free mice. T cells were also required for neurogenic responses in myenteric neurons of the ileum, but not the colon, and for regulating the levels of nestin expression. The cytokines IL-1{beta} and IL-17A mediate the enteric neurogenic response to an SPF microbiota but were not involved in the regulation of intestinal motility. Together, our findings provide new insights into the microbiota-neuroimmune dialogue that regulates intestinal physiology.

physiology↗

bioRxiv2022

Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain

Neuroimmune interactions across the pain pathway play a predominant role in the development of neuropathic pain. Previous reports demonstrated that complement driven effector systems including the C5a/C5aR1 axis contribute to these neuro-immune mechanisms. However, the cellular and molecular mechanisms underlying C5a/C5aR1 signaling-mediated neuropathic pain development remain ill-identified. Here we show that neuropathic pain following peripheral nerve injury was attenuated in C5aR1-deficient male and female mice as well as in wild type mice treated with a selective allosteric C5aR1 antagonist. Using two complementary cell-specific C5aR1 knockout mouse strains, we identified C5a/C5aR1 driven-activation of sensory neuron-associated macrophages (sNAMs) located in the sensory ganglia as the key site of peripheral nerve injury-induced neuropathic pain, whereas activation of macrophages of the local of peripheral nerve injury was not involved. Mechanistically, we uncovered IL-1b the main mediator of pain hypersensitivity in response to C5aR1 signaling in sNAMs. Our findings highlight a crucial role of C5a/C5aR1 axis activation in sNAMs for the development of neuropathic pain and identify this pathway as a promising novel target for neuropathic pain therapy.

pharmacology and toxicology↗

bioRxiv2022

Sensory neuron-associated macrophages proliferate in the sensory ganglia after peripheral nerve injury in a CX3CR1 signaling dependent manner

Resident macrophages are distributed across all tissues and are highly heterogeneous as a consequence of adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophages in the sensory ganglia which have been involved in different conditions, especially in neuropathic pain development and nerve regeneration. However, it is still under debate whether macrophages accumulation in the sensor ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or as a result of blood monocytes infiltration. Here, we confirmed that the number of macrophages increased in the DRGs after spared nerve injury (SNI) model in mice. By using different approaches, we found that the increase in the number of macrophages in the DRGs after SNI is mainly in consequence of the proliferation of resident CX3CR1+ macrophages but not due to infiltration of CCR2+ blood monocytes. These proliferating macrophages are the source of the production of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain and/or nerve regeneration.

immunology↗

bioRxiv2021

Neuroimmune-glial cells interactions elevate the kynurenine metabolic pathway to sustain neuropathic pain

Neuropathic pain is triggered by injury to the somatosensory system, and is one of the most important types of chronic pain. Nevertheless, critical pathophysiological mechanisms that maintain neuropathic pain are poorly understood. Here, we show that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase (IDO) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO upregulation in dendritic cells that accumulate in the dorsal root leptomeninges led to increased levels of kynurenine (Kyn) in the spinal cord, where Kyn is metabolized by astrocytes-expressed kynurenine-3-monooxygenase into a pro-nociceptive metabolite 3-hydroxykynurenine. In conclusion, these data reveal a novel role for KYNPATH as an important factor maintaining neuropathic pain during neuroimmune-glia cells interactions. This novel paradigm offers potential new targets for drug development against this type of chronic pain.

neuroscience↗