The CD20 homolog Ms4a8a integrates pro- and anti-inflammatory signals in novel M2-like macrophages and is expressed in parasite infection.
Recently, we identified the CD20 homolog Ms4a8a as a novel molecule expressed by tumor-associated macrophages that directly enhances tumor growth. Here, we analyzed Ms4a8a(+)  macrophages in M2-associated infectious pathologies. In late-stage Trypanosoma congolense and Taenia crassiceps infections, Ms4a8a expression was detected in hepatic and peritoneal macrophages respectively. Innate immunity in these infections is modulated by Toll-like receptor (TLR) signaling and TLR2/4/7 agonists strongly induced Ms4a8a expression in bone marrow derived macrophages (BMDMs) treated with M2 mediators (glucocorticoids/IL-4). LPS/dexamethasone/IL-4-induced Ms4a8a(+)  BMDMs were characterized by strong expression of mRNA of mannose receptor (Mmr), arginase 1, and CD163, and by decreased iNOS expression. Coinduction of Ms4a8a by M2 mediators and TLR agonists involved the classical TLR signaling cascade via activation of MyD88/TRIF and NF-κB. Forced overexpression of Ms4a8a modulated the TLR4 response of RAW264.7 cells as shown by gene expression profiling. Upregulation of Hdc, Tcfec, and Sla was confirmed both in primary LPS/dexamethasone/IL-4-stimulated Ms4a8a(+)  BMDMs and in peritoneal macrophages from late-stage Taenia crassiceps infection. In conclusion, we show that TLR signaling skews the typical alternative macrophage activation program to induce a special M2-like macrophage subset in vitro that also occurs in immunomodulatory immune reactions in vivo, a process directly involving the CD20 homolog Ms4a8a.
Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. astrid.schmieder@umm.de
Astrid
A
Schmieder
Kai
K
Schledzewski
Julia
J
Michel
Kathrin
K
Schönhaar
Yannick
Y
Morias
Tom
T
Bosschaerts
Jan
J
Van den Bossche
Pierre
P
Dorny
Andrea
A
Sauer
Carsten
C
Sticht
Cyrill
C
Géraud
Zoe
Z
Waibler
Alain
A
Beschin
Sergij
S
Goerdt
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D001119:Arginase / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D007113:Immunity, Innate / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013621:Taenia / Q000276:immunology*; D013622:Taeniasis / Q000276:immunology* / Q000469:parasitology; D051193:Toll-Like Receptors / Q000819:agonists; D014348:Trypanosoma congolense / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology; D000098902:CD163 Antigen
D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D012313:RNA; C544448:Arg1 protein, mouse; D001119:Arginase