Phagocytic receptors activate and immune inhibitory receptor SIRPα inhibits phagocytosis through paxillin and cofilin

Abstract

The innate immune function of phagocytosis of apoptotic cells, tissue debris, pathogens, and cancer cells is essential for homeostasis, tissue repair, fighting infection, and combating malignancy. Phagocytosis is carried out in the central nervous system (CNS) by resident microglia and in both CNS and peripheral nervous system by recruited macrophages. While phagocytosis proceeds, bystander healthy cells protect themselves by sending a “do not eat me” message to phagocytes as CD47 on their surface ligates immune inhibitory receptor SIRPα on the surface of phagocytes and SIRPα then produces the signaling which inhibits phagocytosis. This helpful mechanism becomes harmful when tissue debris and unhealthy cells inhibit their own phagocytosis by employing the same mechanism. However, the inhibitory signaling that SIRPα produces has not been fully revealed. We focus here on how SIRPα inhibits the phagocytosis of the tissue debris “degenerated myelin” which hinders repair in axonal injury and neurodegenerative diseases. We tested whether SIRPα inhibits phagocytosis by regulating cytoskeleton function through paxillin and cofilin since (a) the cytoskeleton generates the mechanical forces that drive phagocytosis and (b) both paxillin and cofilin control cytoskeleton function. Paxillin and cofilin were transiently activated in microglia as phagocytosis was activated. In contrast, paxillin and cofilin were continuously activated and phagocytosis augmented in microglia in which SIRPα expression was knocked-down by SIRPα-shRNA. Further, levels of phagocytosis, paxillin activation, and cofilin activation positively correlated with one another. Taken together, these observations suggest a novel mechanism whereby paxillin and cofilin are targeted to control phagocytosis by both the activating signaling that phagocytic receptors produce by promoting the activation of paxillin and cofilin and the inhibiting signaling that immune inhibitory SIRPα produces by promoting the inactivation of paxillin and cofilin.

Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine

“…To understand how the activation of p38MAPK affects resting microglia functions, paxillin phosphorylation was examined since paxillin has been reported to be a major substrate for p38MAPK and ERK1/2 at Ser 83 residue ( Huang et al, 2004 ). Paxillin, a focal adhesion adaptor protein, is known to be involved in focal adhesion dynamics, cell migration, and phagocytosis ( Tsubouchi et al, 2002 ; Webb et al, 2004 ; Gitik et al, 2014 ). Studies have shown that paxillin interacts with many proteins and these interactions result in changes in the organization of the actin cytoskeleton, which are necessary for controlling phagocytosis and cell motility ( Turner, 2000 ; Duran et al, 2009 ).…”

Differential Spinal and Supraspinal Activation of Glia in a Rat Model of Morphine Tolerance

“…M1/2 microglia activation was not studied previously in the context of chronic morphine administration. We defined M2 microglia according to high expression of CD172a (SIRPa), which has been shown to prevent phagocytosis and to exert anti-inflammatory properties when paired with CD47 (Latour et al, 2001;Barclay and Van den Berg, 2014;Gitik et al, 2014). It should be stated, however, that the concept of M1 and M2 polarization may over-simplify the broad spectrum of microglial activation phenotypes, but also that heterogeneity of microglial populations is not only limited to M1/2 phenotypes (Cherry et al, 2014;Chen and Trapp, 2016;Ransohoff, 2016).…”

Cofilin Inhibition Restores Neuronal Cell Death in Oxygen–Glucose Deprivation Model of Ischemia

“…Furthermore, up-regulation of AC and pyridoxal-5′-phosphate phosphatase/chronophin mediate astroglial apoptosis after status epilepticus [26]. In activated microglia, cofilin is involved in the regulation of NADPH oxidase activity [27] and phagocytosis [28,29]. Accordingly, future studies are warranted to elucidate the role of cofilin in microglial activation and astrocytes during ischemia.…”