Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function

Abstract

Critical functions of immune cells require them to rapidly change their shape and generate forces in response to cues from their surrounding environment. However, little is known about how soluble factors that may be present in the microenvironment modulate key aspects of cellular mechanobiology—such as immune cell deformability and force generation—to impact functions such as phagocytosis and migration. Here we show that signaling by soluble stress hormones through β‐adrenoceptors (β‐AR) reduces the deformability of macrophages; this is dependent on changes in the organization of the actin cytoskeleton and is associated with functional changes in phagocytosis and migration. Pharmacologic interventions reveal that the impact of β‐AR signaling on macrophage deformability is dependent on actin‐related proteins 2/3, indicating that stress hormone signaling through β‐AR shifts actin organization to favor branched structures rather than linear unbranched actin filaments. These findings show that through remodeling of the actin cytoskeleton, β‐AR‐mediated stress hormone signaling modulates macrophage mechanotype to impact functions that play a critical role in immune response.—Kim, T.‐H., Ly, C., Christodoulides, A., Nowell, C. J., Gunning, P. W., Sloan, E. K., Rowat, A. C. Stress hormone signaling through β‐adrenergic receptors regulates macrophage mechanotype and function. FASEB J. 33, 3997–4006 (2019). http://www.fasebj.org

Unraveling the mechanobiology of immune cells

“…For example, stress hormones — epinephrine and norepinephrine — govern fight-or-flight responses by modulating muscle contraction [ 14 ]. Stress hormone activation of the β -adrenergic receptor ( β -AR) signaling pathway further impacts macrophage mechanobiology, decreasing the deformability of macrophage cells through the rearrangement of branched filamentous actin in the cortical region [ 15 ]. Such a decrease in cell deformability induced by β -AR activation is also associated with an increase in macrophage phagocytosis and chemotaxis [ 15 ].…”

“…Stress hormone activation of the β -adrenergic receptor ( β -AR) signaling pathway further impacts macrophage mechanobiology, decreasing the deformability of macrophage cells through the rearrangement of branched filamentous actin in the cortical region [ 15 ]. Such a decrease in cell deformability induced by β -AR activation is also associated with an increase in macrophage phagocytosis and chemotaxis [ 15 ]. Moreover, environmental pathogens can change host cell mechanotypes.…”

Disruption of STAT6 Signal Promotes Cardiac Fibrosis Through the Mobilization and Transformation of CD11b+ Immature Myeloid Cells

“…Further, cardiac macrophages are responsible for impaired myocardial relaxation and aggravated myocardial stiffness while diastolic dysfunction develops (Hulsmans et al, 2018). It is known that β-ARs are expressed on the surface of macrophages in most tissues, and macrophage mechanotype and function can be regulated through β-AR by stress hormone signal (Kim et al, 2019). In this study, the data demonstrated that STAT6 deficiency promotes macrophage differentiation from CD11b + IMCs and recruits them into the injured hearts after chronic stimulation of β-AR, which in turn aggravated cardiac fibrosis.…”

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“…In that sense its effect on the morphological and functional activity of the macrophages merits attention. It has been reported that epinephrine regulates the size, morphology, motility and the capacity for phagocytosis of rat peritoneal macrophages and modulates their immune responses by affecting their capability for cytokine production [6][7][8]. Notably, the kind of cytokines produced by immune cells is related to the type of receptors activated by catecholamines.…”

“…Notably, the kind of cytokines produced by immune cells is related to the type of receptors activated by catecholamines. Stimulation of α-adrenoreceptors induces TNFα and IL-1β production, while incitement of β-adrenoreceptors results in inhibition of TNFα, IL-1β, IL-2, IL-4, IL-6, IL-10 and IL-12 secretion [7,9,10]. It has been shown that stimulation of α2-adrenoreceptor expressed on lamina propria mononuclear cells accelerated the progress of experimental colitis in mice, while their blockade restrained the inflammatory response and ameliorated the progress of the disease [11].…”