title: Genetic ablation of arginase 1 in macrophages and neutrophils enhances clearance of an arthritogenic alphavirus.
abstract: Chikungunya virus (CHIKV) and Ross River virus (RRV) cause a debilitating, and often chronic, musculoskeletal inflammatory disease in humans. Macrophages constitute the major inflammatory infiltrates in musculoskeletal tissues during these infections. However, the precise macrophage effector functions that affect the pathogenesis of arthritogenic alphaviruses have not been defined. We hypothesized that the severe damage to musculoskeletal tissues observed in RRV- or CHIKV-infected mice would promote a wound-healing response characterized by M2-like macrophages. Indeed, we found that RRV- and CHIKV-induced musculoskeletal inflammatory lesions, and macrophages present in these lesions, have a unique gene-expression pattern characterized by high expression of arginase 1 and Ym1/Chi3l3 in the absence of FIZZ1/Relmα that is consistent with an M2-like activation phenotype. Strikingly, mice specifically deleted for arginase 1 in neutrophils and macrophages had dramatically reduced viral loads and improved pathology in musculoskeletal tissues at late times post-RRV infection. These findings indicate that arthritogenic alphavirus infection drives a unique myeloid cell activation program in inflamed musculoskeletal tissues that inhibits virus clearance and impedes disease resolution in an arginase 1-dependent manner.
authors.affiliation: Department of Immunology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Stoermer
authors.forename: Adam
authors.initials: A
authors.lastname: Burrack
authors.forename: Lauren
authors.initials: L
authors.lastname: Oko
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Montgomery
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Morrison
mesh_terms: D018354:Alphavirus Infections / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics*; D002460:Cell Line; D002646:Chikungunya virus / Q000276:immunology*; D006224:Cricetinae; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology / Q000821:virology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D012398:Ross River virus / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*; D019562:Viral Load / Q000276:immunology
chemical_list: C544448:Arg1 protein, mouse; D001119:Arginase