Scavenger Receptor A Dampens Induction of Inflammation in Response to the Fungal PathogenPneumocystis carinii

Abstract

Alveolar macrophages are the effector cells largely responsible for clearance of Pneumocystis carinii from the lungs. Binding of organisms to ␤-glucan and mannose receptors has been shown to stimulate phagocytosis of the organisms. To further define the mechanisms used by alveolar macrophages for clearance of P. carinii, mice deficient in the expression of scavenger receptor A (SRA) were infected with P. carinii, and clearance of organisms was monitored over time. SRA-deficient (SRAKO) mice consistently cleared P. carinii faster than did wild-type control mice. Expedited clearance corresponded to elevated numbers of activated CD4 ؉ T cells in the alveolar spaces of SRAKO mice compared to wild-type mice. Alveolar macrophages from SRAKO mice had increased expression of CD11b on their surfaces, consistent with an activated phenotype. However, they were not more phagocytic than macrophages expressing SRA, as measured by an in vivo phagocytosis assay. SRAKO alveolar macrophages produced significantly more tumor necrosis factor alpha (TNF-␣) than wildtype macrophages when stimulated with lipopolysaccharide in vitro but less TNF-␣ in response to P. carinii in vitro. However, upon in vivo stimulation, SRAKO mice produced significantly more TNF-␣, interleukin 12 (IL-12), and IL-18 in response to P. carinii infection than did wild-type mice. Together, these data indicate that SRA controls inflammatory cytokines produced by alveolar macrophages in the context of P. carinii infection.

Mechanism and Regulatory Function of CpG Signaling via Scavenger Receptor B1 in Primary B Cells

“…For example, it has been shown that scavenger receptor A family members negatively regulate immune activity triggered by tumors, fungal pathogens, and apoptotic cells (11,42,43). In our studies, we have shown that dual engagement of SR-B1 and TLR9 by CpG negatively regulates the production of pro-inflammatory mediators such as IL-6 and IL-10.…”

Scavenger Receptor Class-A Has a Central Role in Cerebral Ischemia–Reperfusion Injury

“…For example, SR-A can recognize several pathogen-associated molecular patterns, such as lipopolysaccharide, lipoteichoic acid, bacterial CpG DNA, double-stranded RNA, and yeast zymosan/b-glucans (Zhu et al, 2001;Mukhopadhyay and Gordon, 2004;Hollifield et al, 2007;Limmon et al, 2008;Areschoug and Gordon, 2008). The contribution of the innate immune and inflammatory responses to cerebral I/R has been well demonstrated (Jordan et al, 2008;Brea et al, 2009).…”

“…Scavenger receptor A has recently been shown to act as a PRR and has an important role in the induction of innate immune and inflammatory responses (Zhu et al, 2001;Hollifield et al, 2007;Limmon et al, 2008). For example, SR-A can recognize several pathogen-associated molecular patterns, such as lipopolysaccharide, lipoteichoic acid, bacterial CpG DNA, double-stranded RNA, and yeast zymosan/b-glucans (Zhu et al, 2001;Mukhopadhyay and Gordon, 2004;Hollifield et al, 2007;Limmon et al, 2008;Areschoug and Gordon, 2008).…”

“…Subsequently, SR-A has been shown to recognize and clear modified host components, apoptotic cells, and pathogens (Platt and Gordon, 2001;Greaves and Gordon, 2009). Numerous studies have shown that SR-A has a critical role in the induction of innate immune and inflammatory responses by recognition of exogenous pathogen-associated molecular patterns and endogenous ligands (Zhu et al, 2001;Hollifield et al, 2007;Limmon et al, 2008). However, the intracellular signaling mediated by SR-A is still unclear.…”

“…Scavenger receptor A is considered to be a PRR (Zhu et al, 2001;Hollifield et al, 2007;Limmon et al, 2008); therefore, we examined whether SR-A is involved in cerebral I/R injury. As shown in Figure 1, focal cerebral I/R resulted in large infarcts in WT mice.…”