Stretching the Function of Innate Immune Cells

Abstract

The importance of innate immune cells to sense and respond to their physical environment is becoming increasingly recognized. Innate immune cells (e.g. macrophages and neutrophils) are able to receive mechanical signals through several mechanisms. In this review, we discuss the role of mechanosensitive ion channels, such as Piezo1 and transient receptor potential vanilloid 4 (TRPV4), and cell adhesion molecules, such as integrins, selectins, and cadherins in biology and human disease. Furthermore, we explain that these mechanical stimuli activate intracellular signaling pathways, such as MAPK (p38, JNK), YAP/TAZ, EDN1, NF-kB, and HIF-1α, to induce protein conformation changes and modulate gene expression to drive cellular function. Understanding the mechanisms by which immune cells interpret mechanosensitive information presents potential targets to treat human disease. Important areas of future study in this area include autoimmune, allergic, infectious, and malignant conditions.

Keywords: Piezo1; TRPV4; innate immunity; integrins; macrophage; mechanotranduction; neutrophil.

Figure 1

Macrophage activation by TRPV4, Piezo1, and Integrins: TRPV4 is activated by both direct (chemical, mechanical) and indirect mechanisms (downstream signaling through interactions with integrins and TLRs, although the exact mechanism has yet to be elucidated). TRPV4 activation leads to Ca²⁺ influx and activation of several nuclear transcription factors, such as MAPK and YAP/TAZ leading to a decrease in pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines, such as IL-10. Activation of Piezo1, either directly or through interaction with TLRs, leads to Ca²⁺ influx, AP-1 activation, production of EDN1, and nuclear translocation of HIF1α and NF-kB leading to an increase in pro-inflammatory cytokines, IL-6 and TNF-α. Feedback loops between Piezo1 and actin polymerization also contribute to macrophage function. Integrins traverse the cell membrane with an extracellular ligand binding site connecting to an intracellular cytoskeletal bind site. Integrins are important for control of viral and bacterial infections through interactions with TLRs. Further study is needed to fully understand the interactive functions of Piezo1 and TRPV4 and their ability to be activated by integrins and TLRs. These interactions are likely cell-type and context specific.