Murine Macrophages Produce Secretory Leukocyte Protease Inhibitor During Clearance of Apoptotic Cells: Implications for Resolution of the Inflammatory Response

Abstract

Macrophage-derived secretory leukocyte protease inhibitor (SLPI) can be induced locally as well as systemically in response to microbial products such as LPS and lipotechoic acid. It is not known whether phagocytosis of apoptotic cells, an essential function of macrophages, can regulate expression and secretion of SLPI. In this study, we report that exposure of peritoneal macrophages of BALB/c mice or murine macrophage cell lines RAW264.7 and J774.1 to apoptotic target cells induced an elevation in SLPI secretion. Secreted SLPI retained its antichymotrypsin activity. SLPI expression in thymuses from BALB/c mice that had been injected with anti-CD3 Ab to induce apoptosis of thymocytes was also elevated both at the mRNA and protein levels. Colchicine, a microtubular inhibitor, blocked the internalization of apoptotic cells by macrophages but not SLPI secretion, suggesting that surface recognition of apoptotic cells is sufficient for the induction of SLPI. Exposure of RAW264.7 cells to apoptotic CTLL-2 cells induced both SLPI and TNF-α, and addition of IFN-γ inhibited SLPI but augmented TNF-α production. Transfection of either the secreted or a nonsecreted form of SLPI into RAW264.7 cells led to suppression of TNF-α production in response to apoptotic cells. Thus, macrophages secrete an increased amount of SLPI when encountering apoptotic cells, which may help to attenuate potential inflammation during clearance of these cells.

Identification of a microglia phenotype supportive of remyelination

“…7B); however, it was absent in white matter microglia of control animals. Secretory leukocyte peptidase inhibitor (Slpi) or ALP has been implicated in the resolution of inflammation and wound healing (Ashcroft et al, 2000;Doumas et al, 2005;Odaka et al, 2003). ALP immunoreactivity in microglia was only detectable at 5WD in the corpus callosum (Fig.…”

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

“…Next, to investigate the role of SOCS1 in the regulation of apoptosis induced by oxidative stress, we have established Jurkat T cell lines stably overexpressing SOCS1 (Jurkat/HA-SOCS1), and examined the effect of SOCS1 on the apoptosis induced by TNF-a and H 2 O 2 . TNF-a was chosen because, as an inflammatory and cytotoxic cytokine, its ROS-generating and apoptosis-inducing effects were reported (Odaka et al, 2003).…”

“…In immune scenarios, ROS are produced and secreted by activated neutrophils and macrophages via NADPH oxidation at inflammation sites, which often provide oxidative microenvironment for T cells (Fialkow et al, 1993;Dang et al, 2006). In addition, macrophage derived inflammatory cytokines such as tumor necrosis factor (TNF)-a induces ROS generation in target cells (Sparwasser et al, 1997;Odaka et al, 2003). Both the exogenous and endogenously produced H 2 O 2 as such are known to affect T-cell functions including gene activation, proliferation and apoptosis by regulating the cellular redox status and/or influencing ROS-regulated proteins including protein tyrosine phosphatases (PTPs) and mitogen-activated protein kinases (MAPKs; Devadas et al, 2002;Reth, 2002;Rusanescu et al, 2005).…”

Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

“…Phagocytosis of apoptotic cells (efferocytosis) is integrally involved with the regulation of the inflammatory response and maintenance of lung homeostasis by 1) removing dead cells before the onset of necrosis (27), by 2) inducing release of anti-inflammatory mediators (27) and antiproteases (28), and by 3) increasing production of growth factors (29,30). Perhaps not surprisingly, impaired efferocytosis appears to be involved in the pathogenesis of a variety of chronic lung and systemic inflammatory diseases because it is defective in systemic lupus erythematosus, rheumatoid arthritis, cystic fibrosis, bronchiectasis, asthma, and chronic obstructive pulmonary disease (COPD) (31)(32)(33)(34)(35)(36)(37).…”