Resolution-phase macrophages possess a unique inflammatory phenotype that is controlled by cAMP.
Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune-mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.
Bystrom
Jonas
J
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.
Evans
Ian
I
Newson
Justine
J
Stables
Melanie
M
Toor
Iqbal
I
van Rooijen
Nico
N
Crawford
Mark
M
Colville-Nash
Paul
P
Farrow
Stuart
S
Gilroy
Derek W
DW
D000818:Animals; D000242:Cyclic AMP / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D020127:Recovery of Function / Q000276:immunology*
D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
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