Journal Article

CCR1 Plays a Critical Role in Modulating Pain through Hematopoietic and Non-Hematopoietic Cells

Brown, Maryanne L., Souza, Donald, Cook, Brian N., Berg, Karen, Panzenbeck, Mark, Stefanopoulos, Dimitria E., Canfield, Melissa, Pelletier, Josephine, Grimaldi, Christine, Adusumalli, Prathima, Kuzmich, Daniel, Fogal, Steven E., Harcken, Christian, Fryer, Ryan M., Allard, Devan, Modis, Louise K., Corradini, Laura, Anderson, Shawn, Harrison, Paul, Muthukumarana, Akalushi, Lewis, Nuruddeen D., Razavi, Hossein

2014

Overview

Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1-/- animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1-/- mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetic Acid / Adenosine / Animal models / Animals / Arthritis, Experimental - genetics / Arthritis, Experimental - immunology / Biology and Life Sciences / Bone Marrow Cells - immunology / Bone Marrow Cells - metabolism / Bone Marrow Transplantation - methods / CC chemokine receptors / CCR1 protein / Cell Movement - genetics / Cell Movement - immunology / Chemokines / Cytokines / Disease / Dopamine / Flow Cytometry / Freund's Adjuvant / Hyperalgesia / Hyperalgesia - chemically induced / Hyperalgesia - genetics / Hyperalgesia - immunology / Immune system / Immunology / Inflammation / Inflammatory diseases / Leukocyte migration / Leukocytes / Leukocytes (neutrophilic) / Leukocytes - immunology / Leukocytes - metabolism / Ligands / Medicine and Health Sciences / Mice, Inbred C57BL / Mice, Knockout / Myeloid cells / Myeloid Cells - immunology / Myeloid Cells - metabolism / Narcotics / Neutrophil Infiltration - genetics / Neutrophil Infiltration - immunology / Neutrophils / Neutrophils - immunology / Neutrophils - metabolism / Pain / Pain - chemically induced / Pain - genetics / Pain - immunology / Pain Measurement - methods / Pain perception / Peritoneum / Peritonitis - genetics / Peritonitis - immunology / Peritonitis - metabolism / Pharmaceutical sciences / Pharmacology / Potassium / Protein transport / Receptors, CCR1 - antagonists & inhibitors / Receptors, CCR1 - genetics / Receptors, CCR1 - immunology / Research and Analysis Methods / Rheumatoid arthritis / Rodents / Trafficking