Regulation of pulmonary inflammation and fibrosis through expression of integrins αVβ3 and αVβ5 on pulmonary T lymphocytes

Luzina, Irina G.; Todd, Nevins W.; Nacu, Natalia; Lockatell, Virginia; Choi, Jung Min; Hummers, Laura K.; Atamas, Sergei P.

doi:10.1002/art.24435

Cited by 71 publications

(97 citation statements)

References 25 publications

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“…2c). In contrast to over-expression of hIL-4d2 or hIL-4, over-expression of an unrelated protein hCCL18, a potent and highly selective chemoattractant of T lymphocytes, [25][26][27] did not change the relative levels of regulatory T cells (Fig. 2c).…”

Section: Replication-deficient Adenovirus-mediated Gene Deliverymentioning

confidence: 90%

“…23 A relative increase in IL-4 and a decrease in IL-4d2 have been associated with better survival in patients with severe sepsis. 24 In this study, we used a replication-deficient adenovirus system [25][26][27] for gene delivery to mouse lung to overexpress human IL-4 or IL-4d2 in vivo. We show that hIL-4 and hIL-4d2 partially share functional activities in mice in vivo with their species-specific counterparts, but they differ from each other in that over-expression of hIL-4d2 appears to have a more pronounced pro-inflammatory effect.…”

Section: Discussionmentioning

confidence: 99%

“…[25][26][27] Briefly, GenBank consensus sequences for these cytokines were used to artificially synthesize (GenScript, Piscataway, NJ) the DNA fragments corresponding to the respective cDNAs. The fragments were subcloned into a shuttle vector, and transferred into a recombinant replication-deficient adenovirus vector (AdV) using RAPAD Ò technology (ViraQuest, North Liberty, IA).…”

Section: Adenoviral Constructsmentioning

confidence: 99%

“…The adenoviruses were instilled intra-tracheally as previously described in detail. [25][26][27] Fluorescence microscopy of unstained lung sections for GFP was used to confirm infectivity in vivo. Quantitative PCR of lung homogenates was used to confirm over-expression of mRNAs for the delivered cytokines.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…Bronchoalveolar lavage (BAL), pulmonary homogenates, histological and immunohistological analyses, and flow cytometry were all performed as previously described. [25][26][27] Multiplex analyses (Luminex, Austin, TX) of cytokine levels in BAL and lung homogenates were performed in triplicate in each sample from each animal, and the mean values and standard deviations were calculated for the triplicates.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

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Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Summary Interleukin‐4 (IL‐4) acts on cultured cells in a species‐specific fashion, although several reports have suggested that human (h) IL‐4 may be functionally active in rodents in vivo. The latter finding, if true, would not only offer possibilities for pre‐clinical testing of novel hIL‐4‐targeting therapies in animals, but also suggests new opportunities for mechanistic studies of IL‐4 and its receptors. Conventional IL‐4 is encoded by four exons, whereas its poorly studied alternatively spliced isoform is encoded by exons 1, 3 and 4 (IL‐4δ2). Replication‐deficient adenovirus‐mediated gene delivery of hIL‐4 isoforms (hIL‐4 or hIL‐4δ2) to mouse lungs caused similar pulmonary infiltration of T and B lymphocytes, but not eosinophils. There were significant differences in the changes of pulmonary cytokine milieu induced by hIL‐4 compared with hIL‐4δ2, with hIL‐4δ2 inducing higher levels of pro‐inflammatory (tumour necrosis factor‐α, IL‐1, and monocyte chemotactic protein‐1) and T helper type 1 (IL‐12 and interferon‐γ) cytokines. There was no elevation in endogenous mouse (m) IL‐4 or mIL‐4δ2 mRNAs, and germ‐line deficiency of mIL‐4 did not affect the degree of pulmonary infiltration. When combined with an ovalbumin model of asthma, hIL‐4δ2 stimulated a greater accumulation of lymphocytes than did hIL‐4. Pulmonary infiltration of lymphocytes induced by expression of hIL‐4 or hIL‐4δ2 was attenuated, but not completely abrogated, by germ‐line deficiency of mIL‐4Rα or murine signal transducer and activator of transcription 6, suggesting that these signalling molecules mediate the in vivo effects of hIL‐4 isoforms in mice. These findings suggest that splice isoforms of human IL‐4 are functionally active in vivo in mice, and partially share the effects of the corresponding species‐specific isoforms.

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Section: Replication-deficient Adenovirus-mediated Gene Deliverymentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Adenoviral Constructsmentioning

confidence: 99%

Section: Animals and Treatmentsmentioning

confidence: 99%

Section: Animals and Treatmentsmentioning

confidence: 99%

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Splice isoforms of human interleukin-4 are functionally active in mice in vivo

et al. 2011

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Remote Tuning of Built‐In Magnetoelectric Microenvironment to Promote Bone Regeneration by Modulating Cellular Exposure to Arginylglycylaspartic Acid Peptide

Liu

Zhang

Yan

et al. 2020

Adv Funct Materials

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Mimicking the endogenous physical microenvironment is a promising strategy for biomaterial‐mediated tissue regeneration. However, precise control of physical cues such as electric/magnetic fields within extracellular environments to facilitate tissue regeneration remains a formidable challenge. Here, remote tuning of the magnetoelectric microenvironment is achieved by a built‐in CoFe2O4/poly(vinylidene fluoridetrifluoroethylene) [P(VDF‐TrFE)] magnetoelectric membrane for effective bone regeneration. The magnetoelectric microenvironment from the nanocomposite membranes promotes osteogenic differentiation of bone marrow mesenchymal stem cells (BM‐MSCs) and enhances bone defect regeneration by increasing cellular exposure and integrin binding to arginylglycylaspartic acid peptide, as predicted by molecular dynamics simulations. Moreover, BM‐MSCs are directed to the osteogenic lineage by osteoimmuomodulation which involves accelerating transition from an initial inflammatory immune response to a pro‐healing regenerative immune response. This work offers a strategy to mimic the magnetoelectric microenvironment for achieving precise and effective tissue regenerative therapies, as well as provides fundamental insights into the biological effects driven by the built‐in magnetoelectric membrane, which can be remotely tuned to precisely modulate osteogenesis in situ.

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Integrin‐Mediated Interactions Control Macrophage Polarization in 3D Hydrogels

Cha

Shin

Leijten

et al. 2017

Adv Healthcare Materials

198

181

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Adverse immune reactions prevent clinical translation of numerous implantable devices and materials. Although inflammation is an essential part of tissue regeneration, chronic inflammation ultimately leads to implant failure. In particular, macrophage polarity steers the microenvironment towards inflammation or wound healing via the induction of M1 and M2 macrophages, respectively. Here, we demonstrated that macrophage polarity within biomaterials can be controlled through integrin mediated interactions between human monocytic THP-1 cells and collagen-derived matrix. Surface marker, gene expression, biochemical and cytokine profiling consistently indicated that THP-1 cells within a biomaterial lacking cell attachment motifs yielded pro-inflammatory M1 macrophages, whereas biomaterials with attachment sites in the presence of IL-4 induced an anti-inflammatory M2 like phenotype and propagated the effect of IL-4 in induction of M2 like macrophages. Importantly, integrin α2β1 played a pivotal role as its inhibition blocked the induction of M2 macrophages. The influence of the microenvironment of the biomaterial over macrophage polarity was further confirmed by its ability to modulate the effect of IL-4 and lipopolysaccharide, which are potent inducers of M2 or M1 phenotypes, respectively. Thus, our study represents a novel, versatile and effective strategy to steer macrophage polarity through integrin mediated three-dimensional (3D) microenvironment for biomaterial-based programming.

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Regulation of pulmonary inflammation and fibrosis through expression of integrins αVβ3 and αVβ5 on pulmonary T lymphocytes

Abstract: Conclusion. Pulmonary infiltrating T lymphocytes may express integrins ␣V␤3 and ␣V␤5 that are necessary for lymphocytic infiltration and T cellassociated TGF␤ activation and collagen accumulation.

Cited by 71 publications

References 25 publications

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Splice isoforms of human interleukin-4 are functionally active in mice in vivo

Remote Tuning of Built‐In Magnetoelectric Microenvironment to Promote Bone Regeneration by Modulating Cellular Exposure to Arginylglycylaspartic Acid Peptide

Integrin‐Mediated Interactions Control Macrophage Polarization in 3D Hydrogels

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