Participação de vias nociceptivas no controle da inflamação aguda neutrofílica

Abstract

The migration and excessive accumulation of neutrophils in inflamed tissue cause damage and loss of tissue function. In arthritis, neutrophils also participate in joint pain by secreting molecules that directly activate peripheral nociceptors, which conduct painful stimuli through the secretion of neurotransmitters. On the other hand, the death of neutrophils by apoptosis is a trigger for the end of inflammation, since the efferocytosis of apoptotic cells by macrophages stimulates the differentiation of macrophages with anti-inflammatory and pro-resolution properties, situations associated with the resolution of inflammation and tissue repair. Considering the close relationship between inflammation and pain in arthritis, it is pertinent to investigate further the involvement of nociceptors and their neurotransmitters in the activity of leukocytes present in inflamed joint tissue. Thus, this study aimed to investigate the role of nociceptors and the neurotransmitter calcitonin gene-related peptide (CGRP) in neutrophil activity and resolution of acute joint inflammatory response using a self- resolving model of antigen-induced arthritis. The results show a high concentration of CGRP in the dorsal root ganglion (DRG) and synovial tissue at a time point associated with the resolution of joint inflammation in this model, corroborated by the concomitant increase in the number of apoptotic neutrophils and efferocytosis of apoptotic bodies by macrophages. In vitro, CGRP induced neutrophil apoptosis in a concentration- dependent manner. However, neutralization of CGRP using a monoclonal antibody showed a slight reduction in apoptosis and efferocytosis. On the other hand, animals that had their TRPV1+ nociceptive fibers desensitized had a higher number of neutrophils in the joint cavity, but with a reduced presence of apoptotic cells, efferocytosis and macrophages with an anti-inflammatory profile (CD206+) compared to animals with preserved fibers. Similarly, treatment with Buprenorphine, a partial opioid agonist of the μ receptor, increased the number of neutrophils but reduced the presence of apoptotic neutrophils and efferocytosis. Thus, these findings indicate that nociceptors and their neurotransmitters released at the inflammatory site can act on leukocytes, impairing the resolution of the inflammatory process.