Apoptotic cells induce arginase II in macrophages, thereby attenuating NO production

Abstract

In recent years it has become apparent that removal of apoptotic cells (AC) by professional phagocytes alters the macrophage phenotype. This change is characterized by attenuated proinflammatory cytokine expression and NO production, which mechanistically remained unexplained. With the intention to explore molecular mechanisms underlying reduced NO formation, we showed that NO production in IFNgamma-stimulated murine RAW264.7 macrophages exposed to AC but not to either necrotic or viable human Jurkat cells was significantly reduced although iNOS expression remained high compared with controls. Analyzing iNOS activity in the cell extracts by using the radioactive L-arginine/citrulline conversion assay revealed increased ornithine production over citrulline in cells exposed to AC. RT-PCR, Western blot, and luciferase reporter analysis supported the idea of an arginase II increase in response to AC. The involvement of arginase in modulating NO formation in response to AC was substantiated by the arginase inhibitor N(omega)-hydroxy-nor-L-arginine. Moreover, knockdown of arginase II by siRNA allowed recovery of NO production. Experiments with AC-conditioned medium demonstrated that a soluble lipid factor, rather than phagocytosis of AC, modulated NO production in macrophages. We conclude that AC release a lipid factor to modulate NO formation in macrophages via arginase II up-regulation, thereby contributing to innate immune regulation.

Dynamics of lung macrophage activation in response to helminth infection

“…Clearance of apoptotic cells may be one of those signals. Although argII expression is largely independent of Th2 cytokine signaling [53], it is strongly induced in macrophages during the incorporation of apoptotic bodies, where it plays a role in inhibiting classical macrophage activation [31]. In addition, post-Nb AAMs strongly up-regulated complement components such as C1q and C3a, which are known to increase the ability of lung macrophages to phagocytize and incorporate SPs and apoptotic granulocytes [38].…”

The effects of nitric oxide on the immune system during Trypanosoma cruzi infection

“…NO can also affect immune responses through its ability to regulate S-nitrosylation of several components of the apoptotic machinery (Okuda et al 1996, Melino et al 1997, Johann et al 2007, Shibata et al 2007). Apoptosis is an important process in lymphocyte homeostasis and maturation in the thymus, as well as in lymphocyte proliferation in the periphery.…”

“…Uptake of apoptotic cells does not induce an inflammatory response. Accordingly, macrophages upregulate arginase II after phagocytosis of apoptotic cells, which regulates NO production by NOS2 (Freire-de-Lima et al 2000, Johann et al 2007). Additionally, L-arginine, the substrate for NO production, can inhibit the programmed cell death of epimastigotes, either by NOS2-dependent production or by the activity of arginine decarboxylase, which produces polyamines that support parasite proliferation (Paveto et al 1995).…”

Apoptotic Cell-Derived Sphingosine-1-Phosphate Promotes HuR-Dependent Cyclooxygenase-2 mRNA Stabilization and Protein Expression

“…This is characterized by, among other factors, the release of anti-inflammatory mediators such as TGF-␤ or PGE 2 , combined with suppression of proinflammatory cytokine production (2-4). Furthermore, recognition of AC by macrophages attenuates the production of radicals such as NO (5) or superoxide, with the latter mechanism requiring activation of peroxisome proliferator-activated receptor-␥ (6). Recently, it was shown that sphingosine-1-phosphate (S1P) is released from AC via sphingosine kinase 2 (SphK2) to promote macrophage survival (4).…”