Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

Abstract

Zhang S, Song L, Wang Y, Herwald H, Thorlacius H. Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury. Am J Physiol Lung Cell Mol Physiol 305: L756 -L763, 2013. First published September 13, 2013 doi:10.1152/ajplung.00220.2013.-Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 proteinprovoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by Ͼ54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections. adhesion; chemokines; inflammation and leukocyte CLINICAL MANIFESTATIONS OF Streptococcus pyogenes infections vary from uncomplicated cases to severe and fatal conditions, such as streptococcal toxic shock syndrome (STSS), which is associated with a mortality exceeding 50% (7, 15). Despite significant investigative efforts, management of patients with STSS is largely restricted to antibiotics and supportive care, which is partly due to an incomplete understanding of the basic pathophysiology in STSS. S. pyogenes express several different virulence factors, including M proteins, of which there are more than 80 different serotypes described in the literature (15,26). The M1 serotype of Streptococcus pyogenes is most commonly linked to STSS (7). Numerous studies have documented that M1 protein is a powerful stimulator of innate immune cells, such as monocytes (26) and neutrophils (15). In addition, the M1 protein has the capacity to induce formation of cytokines (26), chemokines (9), and tissue factor (25), which all contribute to M1 protein-induced edema formation and tissue damage in the lung. Several studies have shown that lung failure is an insidious feature in STSS patie...

Platelet secretion of CXCL4 is Rac1‐dependent and regulates neutrophil infiltration and tissue damage in septic lung damage

“…Neutrophil accumulation at extravascular sites of tissue injury and inflammation is a multistep process mediated by specific adhesion molecules on neutrophils, such as CD162 and Mac‐1 (Asaduzzaman et al ., ; Zhang et al ., ). Herein, we studied whether targeting of CXCL4 could reduce neutrophil up‐regulation of Mac‐1.…”

Rac1-dependent secretion of platelet-derived CCL5 regulates neutrophil recruitment via activation of alveolar macrophages in septic lung injury

“…This notion is also supported by our findings showing that in contrast to CXCL2, CCL5 exerts no direct chemotactic effect on neutrophils. Accumulation of neutrophils at extravascular sites of inflammation is a multistep process facilitated by specific adhesion molecules expressed on neutrophils, including CD162 and Mac-1 [4,50]. Therefore, we examined whether inhibition of CCL5 might control neutrophil activation and expression of Mac-1.…”

Novel regulators of endothelial barrier function

“…The relevance of immune cells as important regulators of lung vascular barrier function is highlighted by the recent observation that inhibition of leukocyteendothelial interaction in lung capillaries and venules by immunoneutralization of the adhesion molecule CD162 not only reduces the accumulation of neutrophils but also attenuates lung edema in murine models of lung injury that was triggered by intravenous injection of streptococcal M1 protein (161). Not only inflammatory cells, but also microparticles released from neutrophils, platelets, or lymphocytes, can increase endothelial permeability and trigger lung vascular barrier failure.…”