Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli

Chuang, Yishan; Hung, Michelle E.; Cangelose, Brianne K; Leonard, Joshua N.

doi:10.1177/1753425916668243

Cited by 69 publications

(52 citation statements)

References 78 publications

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“…Although macrophage responses to various individual stimuli have been characterized, the manner in which macrophages integrate multiple stimuli to arrive at a polarization outcome is relatively less explored (Chuang and Leonard, in ). Thus, we next investigated whether lentiviral IL‐10 promotes an M2 phenotype in macrophages that (a) receive both pro‐M1 and pro‐M2 stimuli simultaneously or (b) are pre‐polarized to an M1 phenotype prior to exposure to pro‐M2 stimuli.…”

Section: Resultsmentioning

confidence: 99%

Lentivirus delivery of IL‐10 to promote and sustain macrophage polarization towards an anti‐inflammatory phenotype

Boehler

Kuo

Shin

et al. 2014

Biotech & Bioengineering

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Gene delivery from biomaterials can create an environment that promotes and guides tissue formation. However, the immune response induced upon biomaterial implantation can be detrimental to tissue regeneration. Macrophages play a central role in mediating early phases of this response, and functional “polarization” of macrophages towards M1 (inflammatory) or M2 (anti-inflammatory) phenotypes may bias the local immune state at the implant site. Since gene delivery from biomaterial scaffolds can confer transgene expression in macrophages in vivo, we investigated whether transduction of macrophages with an IL-10 encoding lentivirus can (1) induce macrophage polarization toward an M2 phenotype even in an pro-inflammatory environment, and (2) prevent a shift in polarization from M2 to M1 following exposure to pro-inflammatory stimuli. IL-10 lentivirus delivery to pre-polarized M1 macrophages reduced TNF-α production 1.5-fold when compared to cells treated with either a control virus or a bolus delivery of recombinant IL-10 protein. IL-10 lentivirus delivery to naïve macrophages reduced the amount of TNF-α produced following an inflammatory challenge by 2.5-fold compared to cells treated with both the control virus and recombinant IL-10. At a mechanistic level, IL-10 lentivirus delivery mediated sustained reduction in NF-κB activation and, accordingly, reduced transcription of TNF-α. In sum, lentiviral delivery of IL-10 to macrophages represents a promising strategy for directing and sustaining macrophage polarization towards an M2 phenotype in order to promote local immune responses that facilitate tissue engineering.

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Section: Resultsmentioning

confidence: 99%

Lentivirus delivery of IL‐10 to promote and sustain macrophage polarization towards an anti‐inflammatory phenotype

Boehler

Kuo

Shin

et al. 2014

Biotech & Bioengineering

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“…1). The difference could be due to post-transcriptional downregulation of Tnf induced by IL-10R signaling [43][44][45][46] , which would diminish TNF protein more than Tnf transcription, and mCherry is a proxy for the latter.…”

Section: Tnf Expression Is Heterogeneous and Involves Intercellular Cmentioning

confidence: 99%

Macrophages employ quorum licensing to regulate collective activation

Muldoon

Chuang

Bagheri³

et al. 2019

Preprint

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Macrophage-initiated inflammation is tightly regulated to eliminate threats such as infections while suppressing harmful immune activation. However, individual cells’ signaling responses to pro-inflammatory cues are heterogeneous; subpopulations emerge with high or low activation states, though why this occurs is unknown. To address this question, we used single-cell tracking and dynamical modeling to develop and validate a revised model for macrophage activation by lipopolysaccharide (LPS) that invokes a mechanism we termquorum licensing. Bimodal phenotypic partitioning of macrophages is primed during the resting state, depends on cumulative history of cell density, is predicted by extrinsic noise in transcription factor expression, and is independent of canonical LPS-induced intercellular feedback in the tumor necrosis factor (TNF) response. Our analysis shows how this density-dependent coupling produces a nonlinear effect on collective TNF production. We speculate that by linking macrophage density to activation, this mechanism could amplify local responses to threats and prevent false alarms.

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“…IL10‐driven macrophage phenotypes contribute to immunosuppressive signaling in a variety of inflammatory states(Chuang, Hung, Cangelose, & Leonard, 2016). How IL10 interfaces with epithelial tissues like the distal alveolar compartment of the lung to promote repair or protection has been elusive given the marginal expression of IL10Ra in lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

et al. 2020

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The connection between aging‐related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10‐deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle‐aged (12 months old) and aged (20–22 months old) IL10‐deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild‐type (WT) controls, the IL10‐deficient lungs from young (4‐month‐old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10‐deficient milieu. Lung macrophages were increased in the aged IL10‐deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2‐polarized bone marrow‐derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10‐deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage‐mediated alveolar epithelial cell survival and B‐cell survival within tertiary lymphoid structures.

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Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli

Cited by 69 publications

References 78 publications

Lentivirus delivery of IL‐10 to promote and sustain macrophage polarization towards an anti‐inflammatory phenotype

Lentivirus delivery of IL‐10 to promote and sustain macrophage polarization towards an anti‐inflammatory phenotype

Macrophages employ quorum licensing to regulate collective activation

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung

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