Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

Abstract

Accumulating evidence suggests that O 3 exposure may contribute to CNS dysfunction. Here, we posit that inflammatory and acute-phase proteins in the circulation increase after O 3 exposure and systemically convey signals of O 3 exposure to the CNS. To model acute O 3 exposure, female Balb/c mice were exposed to 3 ppm O 3 or forced air for 2 h and were studied after 6 or 24 h. Of 23 cytokines and chemokines, only KC/CXCL1 was increased in blood 6 h after O 3 exposure. The acute-phase protein serum amyloid A (A-SAA) was significantly increased by 24 h, whereas C-reactive protein was unchanged. A-SAA in blood correlated with total leukocytes, macrophages, and neutrophils in bronchoalveolar lavage from O 3 -exposed mice. A-SAA mRNA and protein were increased in the liver. We found that both isoforms of A-SAA completely crossed the intact blood-brain barrier, although the rate of SAA2.1 influx was approximately 5 times faster than that of SAA1.1. Finally, A-SAA protein, but not mRNA, was increased in the CNS 24 h post-O 3 exposure. Our findings suggest that A-SAA is functionally linked to pulmonary inflammation in our O 3 exposure model and that A-SAA could be an important systemic signal of O 3 exposure to the CNS.-Erickson,

Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production

“…In the chronic setting, excessive SAA production is a precursor to secondary amyloidosis that can cause serious complications [ 24 ], and amyloid deposits can also accumulate within the brains of patients with systemic amyloidosis, particularly around circumventricular organs that lack a contiguous BBB [ 25 ]. The acute SAA isoforms have been shown to readily cross the intact BBB, where radiolabelled SAA traversed the endothelial barrier to enter the brain parenchyma [ 15 ]. In a recent study, a liver-specific SAA over-expressing transgenic mouse model was used to evaluate whether acute circulating SAA can contribute to neurodegenerative disorders [ 26 ].…”

“…AT-RvD1 allosterically modulates Fpr2 by actively opposing the actions of SAA to resolve lung inflammation and immunopathology [ 12 , 13 ]. Whilst SAA is known to efficiently enter the brain from the circulation [ 15 ], its role in neuroinflammation in the context of respiratory co-infection is unexplored. In addition, as acute inflammation increases Fpr2 expression in primary microglia [ 16 ], pro-resolving mediators that target this receptor may represent an important target for modulating the function of microglia.…”

Resolving Viral-Induced Secondary Bacterial Infection in COPD: A Concise Review

“…The circulating inflammatory mediators that impair cognitive function during AECOPD are not well-characterized. However, circulating SAA can readily cross the intact blood-brain barrier ( 70 ) and excessive production of SAA in a transgenic model resulted in greater deposition in the brain and an increase in brain inflammation ( 71 ). Consistent with this study, we found that in our co-infection model associated with a marked increase in circulating SAA, there was an increase in SAA immuno-reactivity, increased numbers of “activated” amoeboid-shaped microglia and inflammatory cytokine expression in the brain ( 72 ).…”

Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades

“…However, Baranova et al additionally report that (in cell culture) CLA-1/SR-BI ligands "efficiently compete" with SAA for CLA-1/SR-BI binding [63]. (For example, it has already been documented in the literature that both apoA-I and SAA are substrates for SR-BI, which indicates that SR-BI could mediate the transport of both proteins across the BBB (e.g., [65])). Not surprisingly, therefore, Robert et al have recently asserted that many lines of evidence suggest a protective role for HDL and its major apolipoprotein (apo)A-I in Alzheimer's disease [14].…”