Protective role of TRPV1+ nociceptive neurons communication to macrophages against T. cruzi infection in mice

• Published in: Brain, behavior, & immunity. Health behavior, & immunity. Health, 2024-12, Vol.42, p.100897, Article 100897
• Main Authors: Borghi, Sergio M., Malvezi, Aparecida D., Lovo-Martins, Maria Isabel, Fattori, Victor, Zaninelli, Tiago H., Bertozzi, Mariana M., Ferraz, Camila R., Cunha, Thiago M., Casagrande, Rubia, Martins-Pinge, Marli C., Pinge-Filho, Phileno, Verri, Waldiceu A.
• Format: Article
• Language: English
• Subjects: And Chagas' disease; from the Special Issue on Emerging PNI research: future leaders in focus; Edited by Amanda Kentner, Lois Harden, Denis de Melo Soares and Christoph Rummel; Macrophage; Neuroinflammation; Nociceptor neuron; TRPV1; Trypanosoma cruzi
• ISSN: 2666-3546; 2666-3546
• DOI: 10.1016/j.bbih.2024.100897

Chagas’ disease is a life-threatening condition caused by Trypanosoma cruzi. Patients with chronic disease may develop gastrointestinal, neurological, or associated neuro-digestive dysfunctions. CNS invasion by T. cruzi can occur in the acute phase, and its presence in the brain and cerebrospinal fluid was reported. T. cruzi induces nociceptor neuron activation and pain. Nociceptive neurons and macrophage interact in diseases, and this neuroimmune communication has a pivotal role in disease outcome. We investigated, the role of TRPV1+ neurons in experimental T. cruzi infection in mice. T. cruzi forms were observed in the DRG and spinal cord in early stages of acute infection, and intrathecal administration of T. cruzi antigens into spinal cord induced pain. Trpv1 mRNA expression was increased in the DRG of infected mice and targeting TRPV1 reduced T. cruzi-induced pain. TRPV1 nociceptor ablation increased blood parasitemia while TRPV1 knockout mice presented 50% mortality upon infection in a normally non-lethal model. TRPV1 knockout also worsened clinical outcomes (hepatomegaly and megacecum), increased plasmatic Th2 cytokines and nitrite in cardiac tissue, and reduced heart leukocyte infiltration. Conditioned media of capsaicin-stimulated DRG neurons decreased macrophage internalization of T. cruzi, and CGRP receptor antagonism in infected mice reduced pain, increased early parasitemia and promoted 18% mortality. This indicates that soluble mediators released upon nociceptor activation such as CGRP increase macrophage ability to control disease outcome. These data unveil TRPV1+ neurons release CGRP to limit macrophage internalization of T. cruzi, triggering protective mechanisms against T. cruzi infection. •T. cruzi infection induces pain via activation of TRPV1+ neurons.•Activation of TRPV1 induces the release of molecules by neurons, CGRP included.•T. cruzi internalization by macrophages is reduced by neuronal conditioned media.•TRPV1 deletion and antagonizing CGRP receptor diminished host protection.•We unveil that TRPV1+ neurons communicate to immune cells protecting the host.