Delineating the complex mechanistic interplay between NF-κß driven mTOR depedent autophagy and monocyte to macrophage differentiation: A functional perspective.

Autophagy is an extremely essential cellular process aimed to clear redundant and damaged materials, namely organelles, protein aggregates, invading pathogens, etc. through the formation of autophagosomes which are ultimately targeted to lysosomal degradation. In this study, we demonstrated that mTOR dependent classical autophagy is ubiquitously triggered in differentiating monocytes. Moreover, autophagy plays a decisive role in sustaining the process of monocyte to macrophage differentiation. We have delved deeper into understanding the underlying mechanistic complexities that trigger autophagy during differentiation. Intrigued by the significant difference between the protein profiles of monocytes and macrophages, we investigated to learn that autophagy directs monocyte differentiation via protein degradation. Further, we delineated the complex cross-talk between autophagy and cell-cycle arrest in differentiating monocytes. This study also inspects the contribution of adhesion on various steps of autophagy and its ultimate impact on monocyte differentiation. Our study reveals new mechanistic insights into the process of autophagy associated with monocyte differentiation and would undoubtedly help to understand the intricacies of the process better for the effective design of therapeutics as autophagy and autophagy-related processes have enormous importance in human patho-physiology.

MAP Kinase driven actomyosin rearrangement is a crucial regulator of monocyte to macrophage differentiation.

Rearrangement of actin cytoskeleton correlates significantly with the immune responses as the perturbation of cytoskeletal dynamics leads to many immune deficiencies. Mechanistic insights into this correlation remain unknown. Cellular spreading, the most characteristic phenotype associated with monocyte to macrophage differentiation, led us to investigate the contribution of actomyosin dynamics in monocyte differentiation. Our observation revealed that actomyosin reorganization intrinsically governs the process of monocyte to macrophage differentiation. Further, we established that the MAPK-driven signaling pathways regulate the cellular actomyosin dynamics that direct monocyte to macrophage differentiation. We also identified P42/44 Mitogen-Activated Protein Kinase (P42/44 MAPK), P38 Mitogen-Activated Protein Kinase (P38 MAPK), MAP Kinase Activated Protein Kinase 2 (MK-2), Heat Shock Protein 27 (Hsp-27), Lim Kinase (Lim K), non-muscle cofilin (n-cofilin), Myosin Light Chain Kinase (MLCK) and Myosin Light Chain (MLC) as critical components of the signaling network. Moreover, we have shown the involvement of the same signaling cascade in 3D gel-like microenvironment induced spontaneous monocyte to macrophage differentiation and in human blood-derived PBMC differentiation. Our study reveals new mechanistic insights into the process of monocyte to macrophage differentiation.