Growth hormone-mediated reprogramming of macrophage transcriptome and effector functions

Abstract

Macrophages are an important component of the innate immune response. Priming and activation of macrophages is stimulated by cytokines (i.e IFNγ). However, growth hormone (GH) can also stimulate macrophage activation. Based on these observations, the goal of this work was to 1) to compare the transcriptome profile of macrophages activated in vitro with GH and IFNγ, and 2) to assess the impact of GH on key macrophage functional properties like reactive oxygen species (ROS) production and phagosomal proteolysis. To assess the global transcriptional and functional impact of GH on macrophage programming, bone marrow derived macrophages were treated with GH or IFNγ. Our data strongly support a potential link between GH, which wanes with age, and impaired macrophage function. The notable overlap of GH with IFNγ-induced pathways involved in innate immune sensing of pathogens and antimicrobial responses argue for an important role for GH in macrophage priming and maturation. By using functional assays that report on biochemical activities within the lumen of phagosomes, we have also shown that GH alters physiologically relevant processes such as ROS production and proteolysis. These changes could have far reaching impacts on antimicrobial capacity, signaling, and antigen presentation.

Activity of the growth hormone‐releasing hormone antagonist MIA602 and its underlying mechanisms of action in sarcoidosis‐like granuloma

“…GH has an important role in the maturation and activation of macrophages. 30 While the role of the GHRH agonist on T cells was described previously by Khorram et al, 31 the current study suggests an anti-inflammatory role of the GHRH-R antagonist in a macrophage phenotype. Our IHC study shows that PD-1 expression in lung macrophages was significantly reduced in the granuloma sarcoid model, and MIA602 restored PD-1 expression.…”

Activity of the GHRH Antagonist MIA602 and its Underlying Mechanisms of Action in sarcoidosis

“…The in vivo experiments in the sarcoidosis mouse model show that tissue inflammation scores were significantly reduced by MIA602 treatment, and this effect is mainly macrophage dependent. GH has an important role in maturation and activation of macrophages(25). While the role of GHRH agonist on T cells was described previously byKhorram et al (26), the current study suggests an anti-inflammatory role of the GHRH-R antagonist in a macrophage phenotype.…”

Early life nociception is influenced by peripheral growth hormone signaling

“…4) (Lu et al, 2013) (Kumar et al, 2014). It is worth noting that recent work has indicated an opposite effect, demonstrating that activating macrophages in culture with GH also results in an increased pro-inflammatory cytokine release (Schneider et al, 2019). It is likely that GH signaling is used by these effector cells as a homeostatic regulator (Dehkhoda et al, 2018).…”

“…Immune cells that infiltrate injury sites release a variety of cytokines and growth factors during repair that can themselves be pro-nociceptive (Ren and Dubner, 2010) (McMahon et al, 2005) (McMahon et al, 2015 (Basbaum et al, 2009) (Philippou et al, 2012). Interestingly, macrophages in particular are known to use peripheral GH to modulate local inflammation (Govers et al, 1999) (Strous et al, 1996) (Lu et al, 2013) (Schneider et al, 2019). Taken together, altered GH signaling within primary afferent neurons may regulate receptor expression to modulate peripheral sensitization and subsequent pain-like behaviors in coordination with the infiltrating immune cells (Basbaum et al, 2009) (McMahon et al, 2015 (Ford et al, 2019).…”