title: Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance.
abstract: Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169(+) (metallophillic) macrophages, resulting in accumulation and activation of FoxP3(+) Tregs and CD11c(+) dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-β and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Departments of Pediatrics and Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
authors.forename: Buvana
authors.initials: B
authors.lastname: Ravishankar
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.forename: Haiyun
authors.initials: H
authors.lastname: Liu
authors.forename: Kapil
authors.initials: K
authors.lastname: Chaudhary
authors.forename: Jillian
authors.initials: J
authors.lastname: Bradley
authors.forename: Henrique P
authors.initials: HP
authors.lastname: Lemos
authors.forename: Phillip
authors.initials: P
authors.lastname: Chandler
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002465:Cell Movement / Q000502:physiology; D054422:Chemokine CCL22 / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054398:Receptors, CCR4 / Q000235:genetics; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D016207:Cytokines; D054398:Receptors, CCR4; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse
keywords: autoimmunity; migration; regulation; spleen; transplantation