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

Abstract

statement: This article brings out a new insight into the novel mechanisms of monocyte differentiation solely driven by physical micro-environment and adhesion.2 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-activation to facilitate differentiation. In 2D fluid-like micro-environment, adhesion alone is capable of inducing differentiation via the same positive-feedback signalling. Chemical inducer treatment in fluid-like microenvironment, 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. Our findings challenge the notion that adhesion is a result of monocyte differentiation. Rather it's the adhesion which triggers the differentiation of monocytes. MAPK, and NF-being key molecules of multiple signaling pathways, we hypothesize that biochemically inert 3D gel-like microenvironment would also influence other cellular functions. Introduction:Cellular functions are controlled by combinations of autonomous and non-autonomous factors. Non-autonomous factors elicit cellular responses via the cellular micro-environment.The chemical makeup of a cellular micro-environment imparts its response either via the receptor-ligand interaction at the plasma membrane or through the transport of soluble molecules into the cytoplasm. The physical makeup of the micro-environment also influences the functioning of the cells 1 2 3 4 . The functional heterogeneity in the macrophages associated with different tissues is speculated to arise from their heterogeneous micro-environments 5 6 .Inside an organism, cells encounter three distinct type of physical micro-environments i) 3D

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

“…Our previous publications depict that the MAPK-NFκβ 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-NFκβ 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-κβ[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 NFκβwhen 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].…”

Inflammatory cytokines shape a changing DNA methylome in monocytes mirroring disease activity in rheumatoid arthritis

“…We exposed PBMCs isolated from healthy donors to these three cytokines individually and cultured in plates treated with polyhydroxyethylmethacrylate (poly-HEMA). The use of poly-HEMA-coated plates prevents monocyte attachment to plates and the subsequent differentiation of monocytes, which may result in additional differentiation-associated methylation changes 44. Following 4 days of exposure to the aforementioned cytokines, we isolated the monocytic fraction by sorting CD33+CD11b+CD15- cells and carried out DNA methylation profiling (figure 4B).…”

Delineating the complex mechanistic interplay between autophagy and monocyte to macrophage differentiation: a functional perspective

“…1D). Previous work from our group had established that adhesion is necessary and sufficient to drive monocyte differentiation in the 2D/3D microenvironment in the absence of any chemical stimuli(Bhattacharya et al, 2018). Therefore,the promotion of adhesion can drive spontaneous differentiation.…”