Macrophages primed by overnight culture demonstrate a marked stimulation of surfactant protein A degradation

1997 ◽  
Vol 273 (4) ◽  
pp. L831-L839 ◽  
Author(s):  
Sandra R. Bates ◽  
Jin Xu ◽  
Chandra Dodia ◽  
Aron B. Fisher

The current study examined whether long-term culture of macrophages affects their metabolism of surfactant components. Compared with freshly isolated resting macrophages in culture for 1 h, macrophages attached to plastic dishes for 24 h showed evidence of conversion to a “primed” state with 1) an altered morphology characterized by a larger size, ruffled membranes, lamellipodia, and a “foamy” appearance after attachment to glass and 2) a fivefold greater respiratory burst in response to phorbol 12-myristate 13-acetate stimulation. On incubation with iodinated surfactant protein A (SP-A), the 24-h alveolar or tissue macrophages showed a 5- or a 23-fold greater increase in SP-A degradation, respectively, than macrophages cultured for 1 h. Conditioned media experiments demonstrated that the elevated rate of SP-A degradation after prolonged culture was not a result of proteases secreted by the macrophages. Incubation of cells with NH4Cl reduced the degradation of SP-A to a similar extent (to 33% of control values) in resting and primed tissue macrophages. On the other hand, length of time of cell culture did not affect macrophage uptake and degradation of [3H]dipalmitoylphosphatidylcholine in mixed unilamellar liposomes. Thus freshly isolated resting tissue and alveolar macrophages can be primed to specifically increase their rate of SP-A degradation. Activation of macrophages associated with lung disease may be important for SP-A metabolism and surfactant function.

2012 ◽  
Vol 303 (7) ◽  
pp. L608-L616 ◽  
Author(s):  
Huy A. Nguyen ◽  
Murugesan V. S. Rajaram ◽  
Douglas A. Meyer ◽  
Larry S. Schlesinger

Alveolar macrophages (AMs) are exposed to frequent challenges from inhaled particulates and microbes and function as a first line of defense with a highly regulated immune response because of their unique biology as prototypic alternatively activated macrophages. Lung collectins, particularly surfactant protein A (SP-A), contribute to this activation state by fine-tuning the macrophage inflammatory response. During short-term (10 min–2 h) exposure, SP-A's regulation of human macrophage responses occurs through decreased activity of kinases required for proinflammatory cytokine production. However, AMs are continuously exposed to surfactant, and the biochemical pathways underlying long-term reduction of proinflammatory cytokine activity are not known. We investigated the molecular mechanism(s) underlying SP-A- and surfactant lipid-mediated suppression of proinflammatory cytokine production in response to Toll-like receptor (TLR) 4 (TLR4) activation over longer time periods. We found that exposure of human macrophages to SP-A for 6–24 h upregulates expression of IL-1 receptor-associated kinase M (IRAK-M), a negative regulator of TLR-mediated NF-κB activation. Exposure to Survanta, a natural bovine lung extract lacking SP-A, also enhances IRAK-M expression, but at lower magnitude and for a shorter duration than SP-A. Surfactant-mediated upregulation of IRAK-M in macrophages suppresses TLR4-mediated TNF-α and IL-6 production in response to LPS, and IRAK-M knockdown by small interfering RNA reverses this suppression. In contrast to TNF-α and IL-6, the surfactant components upregulate LPS-mediated immunoregulatory IL-10 production, an effect reversed by IRAK-M knockdown. In conclusion, these data identify an important signaling regulator in human macrophages that is used by surfactant to control the long-term alveolar inflammatory response, i.e., enhanced IRAK-M activity.


2015 ◽  
Vol 9 (8) ◽  
pp. 952-962 ◽  
Author(s):  
Zofi McKenzie ◽  
Michaela Kendall ◽  
Rose-Marie Mackay ◽  
Harry Whitwell ◽  
Christine Elgy ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lidan Liu ◽  
Chaim Z. Aron ◽  
Cullen M. Grable ◽  
Adrian Robles ◽  
Xiangli Liu ◽  
...  

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.


Sign in / Sign up

Export Citation Format

Share Document