Syndecan-4 Regulates Early Neutrophil Migration and Pulmonary Inflammation in Response to Lipopolysaccharide

Abstract

Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC-chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-α. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…A role for syndecan-4 in immune responses has been indicated by previous studies revealing inflammation-related phenotypes in syndecan-4 KO mice. [171][172][173][174] Consistent with our findings in LPS-challenged hearts, syndecan-4 expression is rapidly induced in lungs by administration of LPS and Streptococcus pneumonia. 172,174 In these mouse models of bacterial pneumonia, increased levels of neutrophils and chemokines were found in the bronchoalveolar lavage (BAL) fluid of syndecan-4 KO mice.…”

“…[171][172][173][174] Consistent with our findings in LPS-challenged hearts, syndecan-4 expression is rapidly induced in lungs by administration of LPS and Streptococcus pneumonia. 172,174 In these mouse models of bacterial pneumonia, increased levels of neutrophils and chemokines were found in the bronchoalveolar lavage (BAL) fluid of syndecan-4 KO mice. 172,174 In studies by Nikaido et al 172 and Ishiguro et al, 171 lack of syndecan-4 was associated with increased mortality to bacterial challenge and increased levels of circulating proinflammatory cytokines, possibly due to the ability of syndecan-4 to bind and modulate the inhibitory effect of TGF-β1 on IL-1β production in macrophages.…”

“…172,174 In these mouse models of bacterial pneumonia, increased levels of neutrophils and chemokines were found in the bronchoalveolar lavage (BAL) fluid of syndecan-4 KO mice. 172,174 In studies by Nikaido et al 172 and Ishiguro et al, 171 lack of syndecan-4 was associated with increased mortality to bacterial challenge and increased levels of circulating proinflammatory cytokines, possibly due to the ability of syndecan-4 to bind and modulate the inhibitory effect of TGF-β1 on IL-1β production in macrophages. 171 We, however, found no differences in TNFα and IL-1β synthesis between WT and syndecan-4 KO hearts following LPS challenge (Paper II).…”

“…173 Consistently, these studies show that upregulation of syndecan-4 in response to inflammatory stimuli limits the extent of inflammation and tissue injury. Of note, the mechanisms whereby syndecan-4 mediates its protective effects, ranging from neutrophil migration 172,174 to direct modulation of cytokines, 171,173 appear to vary between the different tissues and the nature of the inflammatory reaction. Our findings in Paper I and II suggested that syndecan-4-mediated protection against inflammation-induced cardiac dysfunction was related to the infiltration of immune cells to the heart (discussed below).…”

Heparan Sulfate in the Developing, Healthy, and Injured Lung

“…These differences may reflect insult-dependent roles of heparanase in lung injury: although heparanase knockout mice were protected from polymicrobial sepsis-induced lung injury (16), no such protection was enjoyed after intranasal LPS (46). In contrast, protease induction during direct lung injury onset sheds HSPGs into the alveolar space where they affect lung injury severity by releasing a sulfation-dependent chemokine gradient necessary for alveolar neutrophilic influx and by facilitating resolution of alveolar inflammation (30,47,48). d Ventilator-induced lung injury: although mechanical ventilation is necessary for the supportive care of patients with ARDS, improper use can induce injury across the alveolar endothelium, epithelium, and interstitium.…”