title: CCR1 plays a critical role in modulating pain through hematopoietic and non-hematopoietic cells.
abstract: 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.
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Nuruddeen D
authors.initials: ND
authors.lastname: Lewis
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Akalushi
authors.initials: A
authors.lastname: Muthukumarana
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Fogal
authors.affiliation: Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Corradini
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Dimitria E
authors.initials: DE
authors.lastname: Stefanopoulos
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Prathima
authors.initials: P
authors.lastname: Adusumalli
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Josephine
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Panzenbeck
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Berg
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Canfield
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Cook
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Hossein
authors.initials: H
authors.lastname: Razavi
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Devan
authors.initials: D
authors.lastname: Allard
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Harrison
authors.affiliation: Department of Integrative Toxicology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Grimaldi
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Donald
authors.initials: D
authors.lastname: Souza
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.affiliation: Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Louise K
authors.initials: LK
authors.lastname: Modis
authors.affiliation: Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States of America.
authors.forename: Maryanne L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D019342:Acetic Acid; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D010147:Pain Measurement / Q000379:methods; D010538:Peritonitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D005620:Freund's Adjuvant; D019342:Acetic Acid