Mechano-Immunomodulation: Mechanoresponsive Changes in Macrophage Activity and Polarization

Abstract

In recent years, biomaterial- and scaffold-based immunomodulation strategies were implemented in tissue regeneration efforts for manipulating macrophage polarization (a.k.a. phenotype or lineage commitment, or differentiation). Yet, most of our understanding of macrophage phenotype commitment and phagocytic capacity is limited to how physical cues (extracellular matrix stiffness, roughness, and topography) and soluble chemical cues (cytokines and chemokines released from the scaffold) influence macrophage polarization. In the context of immune response-tissue interaction, the mechanical cues experienced by the residing cells within the tissue also play a critical role in macrophage polarization and inflammatory response. However, there is no compiled study discussing the effect of the dynamic mechanical environment around the tissues on macrophage polarization and the innate immune response. The aim of this comprehensive review paper is 2-fold; (a) to highlight the importance of mechanical cues on macrophage lineage commitment and function and (b) to summarize the important studies dedicated to understand how macrophage polarization changes with different mechanical loading modalities. For the first time, this review paper compiles and compartmentalizes the studies investigating the role of dynamic mechanical loading with various modalities, amplitude, and frequency on macrophage differentiation. A deeper understanding of macrophage phenotype in mechanically dominant tissues (i.e. musculoskeletal tissues, lung tissues, and cardiovascular tissues) provides mechanistic insights into the design of mechano-immunomodulatory tissue scaffold for tissue regeneration.

Keywords: Anti-inflammatory; Immunomodulation; Macrophages; Mechanical strain; Mechanoimmunomodulation; Mechanotransduction; Phagocytic activity; Polarization; Pro-inflammatory; Tissue engineering.

Figure 1.

The schematic representation of a monocyte extravasation into a tissue and macrophage polarization (1) A circulating monocyte from the bloodstream attaches to the endothelial layer and begins to infiltrate into the targeted tissue, (2) Upon extravasation, monocyte differentiates into macrophage (M0), which further exposes to the chemical, physical, and mechanical cues experienced within the targeted tissue, (3) Macrophage polarizes into classically activated (pro-inflammatory; M1) and alternatively activated (anti-inflammatory; M2) phenotype depending on the tissue milieu, (4) Macrophage differentiation is temporal. Macrophage may change its polarization state by time depending on the needs of the tissue.

Figure 2.

Various mechanical loading modalities experienced across the human body

Figure 3.

Mechanical strain-dependent changes in macrophage morphology (A, B, and C) and phenotype (D). (A) Fluorescence images of U937 human macrophages upon without mechanical strain (i), biaxial (ii) and uniaxial (iii) mechanical strain exposure (–100), (B) Scanning electron microscope (SEM) images of murine macrophages cultured under without mechanical strain (i) and uniaxial mechanical strain (ii) conditions (96), (C) Magnified SEM images of U937 human macrophages cultured under without mechanical strain (i) and biaxial mechanical strain (ii) conditions (96), (D) Fluorescence images of human macrophages and its phenotypic state (M1 stained in red and M2 stained in green) under various uniaxial mechanical strain magnitude; 0% (i) , 7% (ii), and 12% (iii) (101). For images at A,B, and C, the arrows indicate the direction of applied mechanical strain.

Figure 4.

The mechanical strain and its exposure time mediated mRNA level of proinflammatory genes in peritoneal macrophages (A) and MIP-2 protein secretion in fetal lung cells (B). (A) The changes in iNOS, COX-2, IL-1β, MIP-1α, and MIP-2 mRNA level with prolonged 20% mechanical strain exposure. * indicated p<0.05, ** indicated p<0.01, *** indicated p<0.001 versus unstretched controls. Error bars represented standard deviation with n=3. (49) (B) MIP-2 production of rat macrophages over time. White columns indicate control, Black columns indicated mechanical loading of 5% and 40 cycles/min, Light grey indicated LPS stimulation, and Dark grey columns indicate mechanical loading of 5% and 40 cycles/min and LPS stimulation. * indicated p<0.05 versus control, ** indicated p<0.05 versus all other groups, # indicated p<0.05 versus the rest of the groups (104)