Surfactant Protein A Prevents IFN-γ/IFN-γ Receptor Interaction and Attenuates Classical Activation of Human Alveolar Macrophages

Abstract

Lung surfactant protein A (SP-A) plays an important function in modulating inflammation in the lung. However, the exact role of SP-A and the mechanism by which SP-A affects IFN-γ–induced activation of alveolar macrophages (aMϕs) remains unknown. To address these questions, we studied the effect of human SP-A on rat and human aMϕs stimulated with IFN-γ, LPS, and combinations thereof and measured the induction of proinflammatory mediators as well as SP-A’s ability to bind to IFN-γ or IFN-γR1. We found that SP-A inhibited (IFN-γ + LPS)–induced TNF-α, iNOS, and CXCL10 production by rat aMϕs. When rat macrophages were stimulated with LPS and IFN-γ separately, SP-A inhibited both LPS-induced signaling and IFN-γ–elicited STAT1 phosphorylation. SP-A also decreased TNF-α and CXCL10 secretion by ex vivo–cultured human aMϕs and M-CSF–derived macrophages stimulated by either LPS or IFN-γ or both. Hence, SP-A inhibited upregulation of IFN-γ–inducible genes (CXCL10, RARRES3, and ETV7) as well as STAT1 phosphorylation in human M-CSF–derived macrophages. In addition, we found that SP-A bound to human IFN-γ (KD = 11 ± 0.5 nM) in a Ca2+-dependent manner and prevented IFN-γ interaction with IFN-γR1 on human aMϕs. We conclude that SP-A inhibition of (IFN-γ + LPS) stimulation is due to SP-A attenuation of both inflammatory agents and that the binding of SP-A to IFN-γ abrogates IFN-γ effects on human macrophages, suppressing their classical activation and subsequent inflammatory response.

Local amplifiers of IL-4Rα–mediated macrophage activation promote repair in lung and liver

“…Surfactant protein A was isolated from BAL of patients with alveolar proteinosis using a sequential butanol and octylglucoside extraction (11, 30–33). The purity of SP-A was checked by one-dimensional SDS-PAGE in 12 % acrylamide under reducing conditions and mass spectrometry.…”

“…The microbicidal activity of native and recombinant human SP-A against Escherichia coli J5 was evaluated by bacterial killing assays as described previously (30). Levels of mouse SP-A from BAL, pleural exudate, or lung tissue were detected by western-blot analysis as reported elsewhere (11, 30–33). Native human C1q was obtained from Abcam (Cambridge, UK).…”

“…The pro-type 2 effects we report here contrast with reports that associate SP-A with protection in asthma (10). However, in addition to promoting M(IL-4) and proliferation of macrophages, the anti-inflammatory properties of SP-A (5, 6, 8, 9, 11) may suppress the strong inflammatory responses that are responsible for more severe asthma. Our data are supported by the finding that SP-D-deficient mice, which lack SP-A (12), also have reduced M(IL-4) responsiveness (13).…”

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

“…e functions of activated macrophages are regulated by mediators produced by T cells. e classically activated macrophages (M1) are regulated by interferon (IFN)-c and LPS [24], while alternatively activated macrophages (M2) are produced in response to IL-4 or IL-13 [25]. M2 macrophages have been shown to play a role in relief of inflammation and thus have decreased capacity to produce cytokines.…”

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

“…Many studies have shown that STAT1 is the key transcriptional mediator of macrophage responses to IFN-γ. [15][16][17] Thus, we mainly focused on the downstream molecules of the STAT1 signaling pathway after IFN-γ stimulation in the following experiments, such as CXCL9 and some proinflammatory cytokines. [17][18][19] We speculated that Grx1/ STAT1-SSG might affect the M1 polarization of macrophages.…”