Discovery of anti-inflammatory physiological peptides that promote tissue repair by reinforcing epithelial barrier formation

Adipose-Derived Stem Cells (ADSC) are present within the hypodermis and are also expected to play a pivotal role in wound healing, immunomodulation, and rejuvenation activities. They orchestrate, through their exosome, the mechanisms associated to cell differentiation, proliferation, and cell migration by upregulating genes implicated in different functions including skin barrier, immunomodulation, cell proliferation, and epidermal regeneration. ADSCs directly interact with their microenvironment and specifically the immune cells, including macrophages and T and B cells, resulting in differential inflammatory and anti-inflammatory mechanisms impacting, in return, ADSCs microenvironment and thus skin function. These useful features of ADSCs are involved in tissue repair, where the required cell proliferation, angiogenesis, and anti-inflammatory responses should occur rapidly in damaged sites. Different pathways involved have been reported such as Growth Differentiation Factor-11 (GDF11), Tumor Growth Factor (TGF)-β, Metalloproteinase (MMP), microRNA, and inflammatory cytokines that might serve as specific biomarkers of their immunomodulating capacity. In this review, we try to highlight ADSCs’ network and explore the potential indicators of their immunomodulatory effect in skin regeneration and aging. Assessment of these biomarkers might be useful and should be considered when designing new clinical therapies using ADSCs or their specific exosomes focusing on their immunomodulation activity.

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Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair

Journal of Experimental Medicine ◽

10.1084/jem.20200667 ◽

2021 ◽

Vol 218 (9) ◽

Author(s):

Matthew DeBerge ◽

Connor Lantz ◽

Shirley Dehn ◽

David P. Sullivan ◽

Anja M. van der Laan ◽

...

Keyword(s):

Myocardial Infarction ◽

Tissue Repair ◽

Myeloid Cell ◽

Selective Inhibition ◽

Mitochondrial Metabolism ◽

Hypoxia Inducible Factors ◽

Low Oxygen ◽

Ischemic Tissue ◽

Anti Inflammatory ◽

Parenchymal Cells

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

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Squalene Stimulates a Key Innate Immune Cell to Foster Wound Healing and Tissue Repair

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/9473094 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Cristina Sánchez-Quesada ◽

Alicia López-Biedma ◽

Estefania Toledo ◽

José J. Gaforio

Keyword(s):

Wound Healing ◽

Inflammatory Cytokines ◽

Tissue Repair ◽

Immune Cell ◽

Critical Role ◽

Virgin Olive Oil ◽

Skin Damage ◽

Macrophage Response ◽

Anti Inflammatory ◽

Minor Compounds

Anti-inflammatory effects of virgin olive oil (VOO) have been described recently, along with its wound healing effect. One of the main minor compounds found in VOO is squalene (SQ), which also possesses preventive effects against skin damage and anti-inflammatory properties. The inflammatory response is involved in wound healing and manages the whole process by macrophages, among others, as the main innate cells with a critical role in the promotion and resolution of inflammation for tissue repair. Because of that, this work is claimed to describe the role that squalene exerts in the immunomodulation of M1 proinflammatory macrophages, which are the first cells implicate in recent injuries. Pro- and anti-inflammatory cytokines were analysed using TPH1 cell experimental model. SQ induced an increase in the synthesis of anti-inflammatory cytokines, such as IL-10, IL-13, and IL-4, and a decrease in proinflammatory signals, such as TNF-α and NF-κB in M1 proinflammatory macrophages. Furthermore, SQ enhanced remodelling and repairing signals (TIMP-2) and recruitment signals of eosinophils and neutrophils, responsible for phagocytosis processes. These results suggest that SQ is able to promote wound healing by driving macrophage response in inflammation. Therefore, squalene could be useful at the resolution stage of wound healing.

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Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

10.1101/612325 ◽

2019 ◽

Author(s):

Bethany M. Young ◽

Keerthana Shankar ◽

Cindy K. Tho ◽

Amanda R. Pellegrino ◽

Rebecca L. Heise

Keyword(s):

Barrier Function ◽

Cellular Response ◽

Alveolar Epithelium ◽

Epithelial Barrier ◽

Epithelial Barrier Function ◽

Main Challenge ◽

Barrier Formation ◽

Epithelial Barriers ◽

Molecular Therapeutic

ABSTRACTDecellularized tissues offer a unique tool for developing regenerative biomaterials orin vitroplatforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen, fibronectin, laminin, and dECM in varying combinations as anin vitrocoating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, E- cadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings reveal potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds or edema related pathologies.

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Anti-Inflammatory Properties of Fructo-Oligosaccharides in a Calf Lung Infection Model and in Mannheimia haemolytica-Infected Airway Epithelial Cells

Nutrients ◽

10.3390/nu13103514 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3514

Author(s):

Yang Cai ◽

Myrthe S. Gilbert ◽

Walter J. J. Gerrits ◽

Gert Folkerts ◽

Saskia Braber

Keyword(s):

Epithelial Cells ◽

A549 Cells ◽

Airway Epithelial Cells ◽

Mannheimia Haemolytica ◽

Epithelial Barrier ◽

Infection Model ◽

Airway Epithelial ◽

Clinical Scores ◽

Lung Infections ◽

Anti Inflammatory

Emerging antimicrobial-resistant pathogens highlight the importance of developing novel interventions. Here, we investigated the anti-inflammatory properties of Fructo-oligosaccharides (FOS) in calf lung infections and in airway epithelial cells stimulated with pathogens, and/or bacterial components. During a natural exposure, 100 male calves were fed milk replacer with or without FOS for 8 weeks. Then, immune parameters and cytokine/chemokine levels in the bronchoalveolar lavage fluid (BALF) and blood were measured, and clinical scores were investigated. Calf primary bronchial epithelial cells (PBECs) and human airway epithelial cells (A549) were treated with Mannheimia haemolytica, lipopolysaccharides (LPS), and/or flagellin, with or without FOS pretreatment. Thereafter, the cytokine/chemokine levels and epithelial barrier function were examined. Relative to the control (naturally occurring lung infections), FOS-fed calves had greater macrophage numbers in BALF and lower interleukin (IL)-8, IL-6, and IL-1β concentrations in the BALF and blood. However, FOS did not affect the clinical scores. At slaughter, FOS-fed calves had a lower severity of lung lesions compared to the control. Ex vivo, FOS prevented M. haemolytica-induced epithelial barrier dysfunction. Moreover, FOS reduced M. haemolytica- and flagellin-induced (but not LPS-induced) IL-8, TNF-α, and IL-6 release in PBECs and A549 cells. Overall, FOS had anti-inflammatory properties during the natural incidence of lung infections but had no effects on clinical symptoms.

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Hypoxia-inducible factor hydroxylase inhibition enhances the protective effects of cyclosporine in colitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00049.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. G90-G97 ◽

Cited By ~ 3

Author(s):

Doug N. Halligan ◽

Mohammed N. Khan ◽

Eric Brown ◽

Catherine R. Rowan ◽

Ivan S. Coulter ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Immune System ◽

Protective Effect ◽

Barrier Function ◽

Epithelial Barrier ◽

Protective Effects ◽

Barrier Dysfunction ◽

Epithelial Barrier Function ◽

Inflammatory Bowel ◽

Anti Inflammatory

Inflammatory bowel disease (IBD) is characterized by epithelial barrier dysfunction with resultant inflammation as the mucosal immune system becomes exposed to luminal antigens. The hydroxylase inhibitor dimethyloxalylglycine (DMOG) reduces symptoms in experimental colitis through the upregulation of genes promoting barrier function and inhibition of epithelial cell apoptosis. The immunosuppressive drug cyclosporine reduces inflammation associated with IBD via suppression of immune cell activation. Given the distinct barrier protective effect of DMOG and the anti-inflammatory properties of cyclosporine, we hypothesized that combining these drugs may provide an enhanced protective effect by targeting both barrier dysfunction and inflammation simultaneously. We used the dextran sulfate sodium model of colitis in C57BL/6 mice to determine the combinatorial efficacy of cyclosporine and DMOG. While cyclosporine and DMOG ameliorated disease progression, in combination they had an additive protective effect that surpassed the level of protection afforded by either drug alone. The ability of DMOG to augment the anti-inflammatory effects of cyclosporine was largely due to preservation of barrier function and at least in part due to zonula occludens-1 regulation. We propose that combining the barrier protective effects of a hydroxylase inhibitor with the anti-inflammatory effects of cyclosporine provides added therapeutic benefit in colitis. NEW & NOTEWORTHY Inflammatory bowel disease is the result of decreased intestinal epithelial barrier function leading to exposure of the mucosal immune system to luminal antigens causing inflammation, which in turn further decreases epithelial barrier function. We demonstrate for the first time that strengthening the epithelial barrier with a hydroxylase inhibitor in combination with the administration of the immunosuppressive cyclosporine provides additive therapeutic advantage in a murine model of colitis

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Comparison of Photobiomodulation and Anti-Inflammatory Drugs on Tissue Repair on Collagenase-Induced Achilles Tendon Inflammation in Rats

Photomedicine and Laser Surgery ◽

10.1089/pho.2017.4364 ◽

2018 ◽

Vol 36 (3) ◽

pp. 137-145 ◽

Cited By ~ 10

Author(s):

Ingvill Fjell Naterstad ◽

Rafael Paolo Rossi ◽

Rodrigo Labat Marcos ◽

Nivaldo Antonio Parizzoto ◽

Lucio Frigo ◽

...

Keyword(s):

Achilles Tendon ◽

Tissue Repair ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Epithelial barrier formation by airway basal cells

Thorax ◽

10.1136/thx.52.3.213 ◽

1997 ◽

Vol 52 (3) ◽

pp. 213-217 ◽

Cited By ~ 27

Author(s):

J. S. Erjefalt ◽

F. Sundler ◽

C. G. Persson

Keyword(s):

Epithelial Barrier ◽

Basal Cells ◽

Barrier Formation

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Circulating Ouabain Modulates Expression of Claudins in Rat Intestine and Cerebral Blood Vessels

International Journal of Molecular Sciences ◽

10.3390/ijms21145067 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5067

Author(s):

Alexander G. Markov ◽

Arina A. Fedorova ◽

Violetta V. Kravtsova ◽

Anastasia E. Bikmurzina ◽

Larisa S. Okorokova ◽

...

Keyword(s):

Tight Junction ◽

Blood Vessels ◽

Barrier Properties ◽

Transepithelial Resistance ◽

Epithelial Barrier ◽

Cerebral Blood Vessels ◽

Down Regulation ◽

Barrier Formation ◽

Tight Junction Permeability

The ability of exogenous low ouabain concentrations to affect claudin expression and therefore epithelial barrier properties was demonstrated previously in cultured cell studies. We hypothesized that chronic elevation of circulating ouabain in vivo can affect the expression of claudins and tight junction permeability in different tissues. We tested this hypothesis in rats intraperitoneally injected with ouabain (1 μg/kg) for 4 days. Rat jejunum, colon and brain frontal lobes, which are variable in the expressed claudins and tight junction permeability, were examined. Moreover, the porcine jejunum cell line IPEC-J2 was studied. In IPEC-J2-cells, ouabain (10 nM, 19 days of incubation) stimulated epithelial barrier formation, increased transepithelial resistance and the level of cSrc-kinase activation by phosphorylation, accompanied with an increased expression of claudin-1, -5 and down-regulation of claudin-12; the expression of claudin-3, -4, -8 and tricellulin was not changed. In the jejunum, chronic ouabain increased the expression of claudin-1, -3 and -5 without an effect on claudin-2 and -4 expression. In the colon, only down-regulation of claudin-3 was observed. Chronic ouabain protected the intestine transepithelial resistance against functional injury induced by lipopolysaccharide treatment or by modeled acute microgravity; this regulation was most pronounced in the jejunum. Claudin-1 was also up-regulated in cerebral blood vessels. This was associated with reduction of claudin-3 expression while the expression of claudin-5 and occludin was not affected. Altogether, our results confirm that circulating ouabain can functionally and tissue-specifically affect barrier properties of epithelial and endothelial tissues via Na,K-ATPase-mediated modulation of claudins expression.

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Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

Cell Death and Differentiation ◽

10.1038/s41418-020-00652-4 ◽

2020 ◽

Author(s):

Ryan G. Snodgrass ◽

Yvonne Benatzy ◽

Tobias Schmid ◽

Dmitry Namgaladze ◽

Malwina Mainka ◽

...

Keyword(s):

Gene Expression ◽

Tissue Repair ◽

Cell Function ◽

Immune Cell ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Th2 Cytokines ◽

Alternatively Activated Macrophages ◽

Anti Inflammatory ◽

Alternatively Activated

Abstract Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.

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