title: CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells.
abstract: Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis (MS). We investigated the role of interleukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages (aaMphis), in an IL-4-dependent manner. This aaMphi phenotype extended to the lack of nitric oxide (NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaMphi phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.
authors.affiliation: BloodCenter of Wisconsin, Blood Research Institute, Milwaukee, Wisconsin 53201-2178, USA.
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Ponomarev
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Maresz
authors.forename: Yanping
authors.initials: Y
authors.lastname: Tan
authors.forename: Bonnie N
authors.initials: BN
authors.lastname: Dittel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000172:deficiency / Q000502:physiology*; D037102:Lectins / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4; D037102:Lectins; D020932:Nerve Growth Factor; D009569:Nitric Oxide; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D001619:beta-N-Acetylhexosaminidases; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C413576:Retnla protein, mouse; C429541:Chil3 protein, mouse