IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo

Abstract

BackgroundMyeloid cells, such as macrophages and microglia, play a crucial role in neuroinflammation and have been recently identified as a novel therapeutic target, especially for chronic forms. The general aim would be to change the phenotype of myeloid cells from pro- to anti-inflammatory, favoring their tissue-trophic and regenerative functions. Myeloid cells, however, display a number of functional phenotypes, not immediately identifiable as pro- or anti-inflammatory, and associated to ambiguous markers.MethodsWe employed in vitro assays to study macrophage polarization/differentiation in the presence of classical polarizing stimuli such as IFNγ (pro-inflammatory) and IL4 (anti-inflammatory). We induced neuroinflammation in mice by immunization with a myelin antigen and treated diseased mice with intracisternal delivery of an IL4-expressing lentiviral vector. We analyzed clinical, pathological, and immunological outcomes with a focus on myeloid cells.ResultsWe found that IL6, usually considered a pro-inflammatory cytokine, was released in vitro by macrophages treated with the anti-inflammatory cytokine IL4. We show the existence of macrophages expressing IL6 along with classical anti-inflammatory markers such as CD206 and demonstrate that these cells are immunosuppressive in vitro. In neuroinflamed mice, we show that IL4 delivery in the central nervous system (CNS) is associated with clinical and pathological protection from disease, associated with increased IL6 expression in infiltrating macrophages.ConclusionsIL6 is known to mediate both pro- and anti-inflammatory effects, having two distinct ways to induce cell-signaling: either through the membrane bound receptor (anti-inflammatory) or through trans-signaling (pro-inflammatory). We show here that IL6-expressing macrophages are associated to protection from neuroinflammation, suggesting that IL6 anti-inflammatory properties prevail in the CNS, and calling for a general reconsideration of IL6 in macrophage polarization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0596-5) contains supplementary material, which is available to authorized users.

Mechanisms Involved in the Remyelinating Effect of Sildenafil

“…In vivo experiments have shown that treatent of mice with LPS increases proinflammatory cytokines including IL-1β, but also IL-4R and further treatment with IL-4 induced the expression of Arg-1 as well as IL-1β, and this unique phenotype was able to promote neurite growth and spinal cord injury recovery (Fenn et al 2014). Furthermore, macrophages treated with IL-4 in vitro, were shown to produce IL-6 while co-expressing the M2 characteristic molecule CD206, and the co-expression of IL-6 did not affect immunosuppressive properties of the M2 phenotype macrophages (Casella et al 2016). Other studies aimed at characterizing specific molecules to delineate and identify microglia /macrophage phenotypes have also shown co-expression of the antiand pro-inflammatory phenotype markers (Chhor et al 2013, Gensel andZhang 2015).…”

“…Nowadays increasing evidence of mixed or overlapping microglia/macrophage phenotype can be found, and has been associated with the recovery after damage. IL-4 treatment of macrophages in vitro produced IL-6 and co-expressed CD206 (M2 marker) without affecting immunosuppressive properties of M2 phenotype macrophages (Casella et al 2016). Moreover, the expression of Arg-1 as well as IL-1β was associated with neurite growth promotion and spinal cord injury recovery (Fenn et al 2014).…”

“…Moreover, the expression of Arg-1 as well as IL-1β was associated with neurite growth promotion and spinal cord injury recovery (Fenn et al 2014). IL-4 gene therapy to EAE mice decreased demyelination and axonal loss showing an increase in the expression of CD206 in microglia/macrophages, but also an increase IL-6 (Casella et al 2016). Even more, it has comes to light evidence that a proinflammatory environment at the beginning of the lesion followed by antiinflammatory environment with increase of pro-resolving and tissue regenerating molecules is required for an effective resolution and repair after CNS injury (Rawji et al 2016) and that the whole spectrum of microglia/macrophage phenotypes are required in the resolution of CNS injury Zhang 2015, Rawji et al 2016).…”

Different Effect by Different Starting Time Point of Exercise of the Nerve Regeneration after the Peripheral Nerve Injury

“…However, the roles of macrophage polarization in peripheral nerve injury and exercise have not been studied to date.Activation of the ligand-activated nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) exerts beneficial effects through regulating the expression of genes relevant to inflammation, and to the monocyte/macrophages [12]. The pharmacological activation of PPAR-γ using high-affinity thiazolidinedione ligands can enhance IL-4-mediated priming of primary monocytes for differentiation towards an M2 macrophage phenotype in vitro (as measured by phenotypic marker studies involving the M2 marker the Mannose Receptor (MR) [13]. Recent study reports that low-intensity exercise can significantly increase PPAR-γ gene expression and activity in human leukocytes, cells that include circulating mono-cytes.…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…IL-6 is required for the development of protective immunity to this pathogen, whereas IL-27 is required to limit infection-induced pathology [383] . IL-6 is known to mediate both pro-and antiinflammatory effects having two distinct ways to induce cell-signaling: either through the membrane bound receptor (antiinflammatory) or through trans-signaling (proinflammatory) [384] . This cytokine is the main stimulator of the production of most acute phase proteins [385,386] , and is important to the transition between acute and chronic inflammation [387] .…”