Differential ability of proinflammatory and anti-inflammatory macrophages to perform macropinocytosis

Abstract

Although anti-inflammatory macrophages perform macropinocytosis constitutively, proinflammatory macrophages do not, due to impaired signaling of the calcium-sensing receptor. However, macropinocytosis can be elicited in proinflammatory macrophages by agonists that induce the recruitment of phosphatidylinositol 3-kinase to the plasma membrane.

Macropinocytosis: New Insights Into Its Underappreciated Role in Innate Immune Cell Surveillance

“…The question of whether or not the constitutive ruffling of phagocytes was initiated and maintained by an ever present external stimulus or was the result of a cell intrinsic constitutively active driver of membrane protrusions had remained a mystery until very recently. In a study comparing growth factor induced and constitutive macropinocytosis in primary human monocyte-derived macrophages and primary human monocyte-derived dendritic cells, it was shown that extracellular calcium is the driver of constitutive macropinocytosis ( 6 , 9 macropinocytosis or phagocytosis ). Extracellular calcium is sensed through the G protein-coupled receptor (GPCR) calcium sensing receptor (CaSR), which upon ligation results in the transient generation of key lipid mediators on the cytosolic leaflet of the plasma membrane—notably phosphatidic acid (PtdOH) and phosphatidylinositol 3,4,5- tris phosphate [PtdIns(3,4,5)P 3 ].…”

“…Constitutive macropinocytosis, for example, requires the presence of extracellular calcium, is less sensitive to perturbations in intracellular/cytosolic pH and forms morphologically distinct macropinosomes [for a detailed comparison of growth-factor induced and constitutive macropinocytosis, please see reference ( 6 )]. Moreover, constitutive macropinocytosis appears to be restricted to primary innate immune cells, most often immature dendritic cells and macrophages, and has been observed in these cell types both in vitro and in vivo ( 7 – 9 ). The rate at which constitutive macropinocytosis occurs is staggering.…”

Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

“…Owing to their anti-inflammatory predisposition, this subset of macrophages is poised to survey, sample and discriminate a variety of host-or pathogen-associated molecules, without eliciting unneeded inflammation, in a manner similar to immature dendritic cells [45]. To this end, anti-inflammatory macrophages readily perform constitutive as well as induced macropinocytosis ( figure 1d and [48,61]). As discussed in more detail in §6, these two types of macropinocytosis differ in their mode of induction and signalling (figure 1b).…”

PI3Kβ is selectively required for growth factor-stimulated macropinocytosis

“…In Dictyostelium, patches of PIP 3 form prior to the organization of the macropinocytic cup, placing PI3K activation at an early stage in the process (Veltman et al, 2016). Similarly, PI3K activation leads to the activation of Rac1 and Pak1, whose constitutive activation in mammalian cells is sufficient to activate macropinocytosis (Dharmawardhane et al, 2000;Hodakoski et al, 2019;Redka et al, 2018), presumably via stimulation of actindependent ruffling. However, PI3Ks are also involved in the later steps of macropinosome formation, as the sequential production of PIP 3 and PI(3,4)P 2 in macropinocytotic cups is required for sealing and scission (Maekawa et al, 2014;Welliver and Swanson, 2012;Yoshida et al, 2009).…”