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

Chagas' disease is a life-threatening condition caused by <i>Trypanosoma cruzi</i>. Patients with chronic disease may develop gastrointestinal, neurological, or associated neuro-digestive dysfunctions. CNS invasion by <i>T. cruzi</i> can occur in the acute phase, and its presence in the brain and cerebrospinal fluid was reported. <i>T. cruzi</i> 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 <i>T. cruzi</i> infection in mice. <i>T. cruzi</i> forms were observed in the DRG and spinal cord in early stages of acute infection, and intrathecal administration of <i>T. cruzi</i> antigens into spinal cord induced pain. <i>Trpv1</i> mRNA expression was increased in the DRG of infected mice and targeting TRPV1 reduced <i>T. cruzi</i>-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 <i>T. cruzi</i>, 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 <i>T. cruzi</i>, triggering protective mechanisms against <i>T. cruzi</i> infection.