3D micro-environment regulates NF-κβ dependent adhesion to induce monocyte differentiation

Abstract

Differentiation of monocytes entails their relocation from blood to the tissue, hence accompanied by an altered physicochemical micro-environment. While the mechanism by which the biochemical make-up of the micro-environment induces differentiation is known, the fluid-like to gel-like transition in the physical micro-environment is not well understood. Monocytes maintain non-adherent state to prevent differentiation. We establish that irrespective of the chemical makeup, a 3D gel-like micro-environment induces a positive-feedback loop of adhesion-MAPK-NF-κβ activation to facilitate differentiation. In 2D fluid-like micro-environment, adhesion alone is capable of inducing differentiation via the same positive-feedback signaling. Chemical inducer treatment in fluid-like micro-environment, increases the propensity of monocyte adhesion via a brief pulse of p-MAPK. The adhesion subsequently elicit differentiation, establishing that adhesion is both necessary and sufficient to induce differentiation in 2D/3D micro-environment. MAPK, and NF-κβ being key molecules of multiple signaling pathways, we hypothesize that biochemically inert 3D gel-like micro-environment would also influence other cellular functions.

Bacterial hopanoids: a newly identified potent inducer of monocyte to macrophage differentiation

“…Our previous publications depict that the MAPK-NF signaling pathway is a crucial regulator of monocyte to macrophage differentiation [45,46].Commensuratewith other reports, we have also shown that inhibition of the activation of this signaling cascade abates differentiation.In this manuscript, our results suggest that hopanoids treatment also leads to the activation of MAPK-NFsignaling pathway for the induction of monocyte to macrophage differentiation.…”

“…The differentiation process is ushered by the activation of a variety of signaling networks that command the various cellular changes. We along with other groups havealsoreported a plethora of signaling molecules contributing to the differentiation process notably MAP kinases and NF- [45,46]. We investigated the involvement of these signaling molecules in the differentiation process induced by the probable hopanoids and our Western blot data suggests the occurrence of phosphorylation of P42/44, P38 MAP kinases as well as NFκwhen treated with the probable hopanoidsvs the untreated control (Fig.6A).…”

“…They also have a lesser number of filopodia as well as membrane-bound cytosolic organelles. On the other hand, differentiating cells exhibit an enlargedsize, numerouscytoplasmic projections, enhanced spreading ability, autophagy induction as well as altered surface protein expression profile [10] [11] [12,13]. As a crucial regulator of the innate immune system differentiated macrophages engulf foreign pathogens like fungi, bacteria, and protozoans [1].…”

Mimicking of Blood Flow Results in a Distinct Functional Phenotype in Human Non-Adherent Classical Monocytes

“…In our model, we avoided the adherence of monocytes to the plate surface, and all harvested cells were non-adherent. According to the described adhesion cascade [ 23 ] and the absence of additional inflammatory stimuli such as interferon-gamma or IL-4 [ 6 ], a differentiation of GM-CSF-activated monocytes to macrophages under dynamic but not under static conditions seems unlikely.…”

Upregulated Interleukin 21 Receptor Enhances Proliferation and Epithelial-Mesenchymal Transition Process in Benign Prostatic Hyperplasia

“…A previous study has supposed macrophages secrete cytokines, such as TGFβ, to induce the proliferation and EMT process of BPH-1 cells via co-culture of BPH-1 cells with macrophages (31). LPS was established as a chemical inducer to differentiate THP-1 cells into macrophages (32). Therefore, LPS was used for differentiation of THP-1 cells in our study.…”