Deconstructing Immune Microenvironments of Lymphoid Tissues for Reverse Engineering

Witzel, Ini Isabée; Nasser, Rasha Ayman; Garcia-Sabaté, Anna; Sapudom, Jiranuwat; Ma, Caihong; Chen, Weiqiang; Teo, Jeremy C. M.

doi:10.1002/adhm.201801126

Cited by 12 publications

(15 citation statements)

References 261 publications

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“…Macrophages are vital innate immune cells with remarkable plasticity that allow them to respond efficiently to pro-and anti-inflammatory signals within their microenvironment [1,2]. Their phenotype and physiology can be altered by the cytokine secretion profile of other cells in the microenvironment in order to modulate the innate and adaptive immune responses [3].…”

Section: Introductionmentioning

confidence: 99%

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

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Monocytes circulate in the bloodstream, extravasate into the tissue and differentiate into specific macrophage phenotypes to fulfill the immunological needs of tissues. During the tissue repair process, tissue density transits from loose to dense tissue. However, little is known on how changes in tissue density affects macrophage activation and their cellular functions. In this work, monocytic cell line THP-1 cells were embedded in three-dimensional (3D) collagen matrices with different fibril density and were then differentiated into uncommitted macrophages (MPMA) using phorbol-12-myristate-13-acetate (PMA). MPMA macrophages were subsequently activated into pro-inflammatory macrophages (MLPS/IFNγ) and anti-inflammatory macrophages (MIL-4/IL-13) using lipopolysaccharide and interferon-gamma (IFNγ), and interleukin 4 (IL-4) and IL-13, respectively. Although analysis of cell surface markers, on both gene and protein levels, was inconclusive, cytokine secretion profiles, however, demonstrated differences in macrophage phenotype. In the presence of differentiation activators, MLPS/IFNγ secreted high amounts of IL-1β and tumor necrosis factor alpha (TNFα), while M0PMA secreted similar cytokines to MIL-4/IL-13, but low IL-8. After removing the activators and further culture for 3 days in fresh cell culture media, the secretion of IL-6 was found in high concentrations by MIL-4/IL-13, followed by MLPS/IFNγ and MPMA. Interestingly, the secretion of cytokines is enhanced with an increase of fibril density. Through the investigation of macrophage-associated functions during tissue repair, we demonstrated that M1LPS/IFNγ has the potential to enhance monocyte infiltration into tissue, while MIL-4/IL-13 supported fibroblast differentiation into myofibroblasts via transforming growth factor beta 1 (TGF-β1) in dependence of fibril density, suggesting a M2a-like phenotype. Overall, our results suggest that collagen fibril density can modulate macrophage response to favor tissue functions. Understanding of immune response in such complex 3D microenvironments will contribute to the novel therapeutic strategies for improving tissue repair, as well as guidance of the design of immune-modulated materials.

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Section: Introductionmentioning

confidence: 99%

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Sapudom¹,

Mohamed

Garcia-Sabaté³

et al. 2020

Bioengineering

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“…It is worth noting that after the removal of polarizing media, macrophages are no longer forced into their intended M1 or M2 phenotype. Instead, they are malleable [ 96 ], straddling between the M1 and M2 boundaries according to their specific responses to oxLDL and their microenvironment. The same applies to M1 as well as M0, because of their plasticity, their phenotypes are dynamic and non-binary [ 25 ], making investigations into atherosclerosis complex, as observed in this study.…”

Section: General Discussion and Conclusionmentioning

confidence: 99%

Biomimetic 3D Models for Investigating the Role of Monocytes and Macrophages in Atherosclerosis

Garcia-Sabaté¹,

Mohamed

Sapudom³

et al. 2020

Bioengineering

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Atherosclerosis, the inflammation of artery walls due to the accumulation of lipids, is the most common underlying cause for cardiovascular diseases. Monocytes and macrophages are major cells that contribute to the initiation and progression of atherosclerotic plaques. During this process, an accumulation of LDL-laden macrophages (foam cells) and an alteration in the extracellular matrix (ECM) organization leads to a local vessel stiffening. Current in vitro models are carried out onto two-dimensional tissue culture plastic and cannot replicate the relevant microenvironments. To bridge the gap between in vitro and in vivo conditions, we utilized three-dimensional (3D) collagen matrices that allowed us to mimic the ECM stiffening during atherosclerosis by increasing collagen density. First, human monocytic THP-1 cells were embedded into 3D collagen matrices reconstituted at low and high density. Cells were subsequently differentiated into uncommitted macrophages (M0) and further activated into pro- (M1) and anti-inflammatory (M2) phenotypes. In order to mimic atherosclerotic conditions, cells were cultured in the presence of oxidized LDL (oxLDL) and analyzed in terms of oxLDL uptake capability and relevant receptors along with their cytokine secretomes. Although oxLDL uptake and larger lipid size could be observed in macrophages in a matrix dependent manner, monocytes showed higher numbers of oxLDL uptake cells. By analyzing major oxLDL uptake receptors, both monocytes and macrophages expressed lectin-like oxidized low-density lipoprotein receptor-1 (LOX1), while enhanced expression of scavenger receptor CD36 could be observed only in M2. Notably, by analyzing the secretome of macrophages exposed to oxLDL, we demonstrated that the cells could, in fact, secrete adipokines and growth factors in distinct patterns. Besides, oxLDL appeared to up-regulate MHCII expression in all cells, while an up-regulation of CD68, a pan-macrophage marker, was found only in monocytes, suggesting a possible differentiation of monocytes into a pro-inflammatory macrophage. Overall, our work demonstrated that collagen density in the plaque could be one of the major factors driving atherosclerotic progression via modulation of monocyte and macrophages behaviors.

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“…The immune system is an expansive and complex network of cells that protects our body against infection. Here, we provide a brief overview of the immune system as detailed reviews of the immune system are already in published work [35][36][37][38] and constantly updated. The human immune system is divided into two parts: the innate immune system and the adaptive immune system (Figure 2).…”

Section: Immune Cells and Microgravitymentioning

confidence: 99%

May the Force Be with You (Or Not): The Immune System under Microgravity

ElGindi

Sapudom

Ibrahim

et al. 2021

Cells

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All terrestrial organisms have evolved and adapted to thrive under Earth’s gravitational force. Due to the increase of crewed space flights in recent years, it is vital to understand how the lack of gravitational forces affects organisms. It is known that astronauts who have been exposed to microgravity suffer from an array of pathological conditions including an impaired immune system, which is one of the most negatively affected by microgravity. However, at the cellular level a gap in knowledge exists, limiting our ability to understand immune impairment in space. This review highlights the most significant work done over the past 10 years detailing the effects of microgravity on cellular aspects of the immune system.

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Deconstructing Immune Microenvironments of Lymphoid Tissues for Reverse Engineering

Cited by 12 publications

References 261 publications

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Collagen Fibril Density Modulates Macrophage Activation and Cellular Functions during Tissue Repair

Biomimetic 3D Models for Investigating the Role of Monocytes and Macrophages in Atherosclerosis

May the Force Be with You (Or Not): The Immune System under Microgravity

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