Genes Involved in the Balance between Neuronal Survival and Death during Inflammation

Abstract

Glucocorticoids are potent regulators of the innate immune response, and alteration in this inhibitory feedback has detrimental consequences for the neural tissue. This study profiled and investigated functionally candidate genes mediating this switch between cell survival and death during an acute inflammatory reaction subsequent to the absence of glucocorticoid signaling. Oligonucleotide microarray analysis revealed that following lipopolysaccharide (LPS) intracerebral administration at striatum level, more modulated genes presented transcription impairment than exacerbation upon glucocorticoid receptor blockage. Among impaired genes we identified ceruloplasmin (Cp), which plays a key role in iron metabolism and is implicated in a neurodegenative disease. Microglial and endothelial induction of Cp is a natural neuroprotective mechanism during inflammation, because Cp-deficient mice exhibited increased iron accumulation and demyelination when exposed to LPS and neurovascular reactivity to pneumococcal meningitis. This study has identified genes that can play a critical role in programming the innate immune response, helping to clarify the mechanisms leading to protection or damage during inflammatory conditions in the CNS.

Therapeutic Potential of Everolimus on Core Autism Symptoms and Increasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis

“…In respect to the association between Cp and Tf, a previous review article suggested that the transfer of iron was regulated by both CP and Tf and that activity of Cp was modulated by Tf [47]. Cp plays a important role in iron metabolism [48]. These strands support the present finding that everolimus might act mTOR signaling by increasing serum levels of Cp and Tf.…”

Neuronal expression of Cd36, Cd44, and Cd83 antigen transcripts maps to distinct and specific murine brain circuits

“…As detailed above, CD36 seems to be multifunctional in terms of signaling, phagocytosis, and lipid metabolism, and its induction by intracerebrally delivered LPS in the CNS is greatly restricted (Rivest et al, unpublished data). According to our previous microarray study (Glezer et al, 2007), Cd44 is among the genes highly induced upon LPS stimulation, whereas Cd83-associated transcript is limited to a small myeloid population in conditions under which antiinflammatory feedback is absent. CD44 function is most related to adhesion, and it has been correlated with ␥-secretase signaling, which is relevant to Alzheimer's disease pathology (Koo and Kopan, 2004).…”

“…Indeed, Cd83 mRNA has long been known to be expressed in brain tissue according to Northern blot experiments (Twist et al, 1998), but the cellular site of expression was never explored. We previously reported that Cd44 and Cd83 transcripts are induced in brain Iba-1-positive myeloid cells by LPS in an endogenous glucocorticoid (GC)-dependent manner and in the absence of GCs signaling, respectively (Glezer et al, 2007). In addition, CD44 protein expression was carefully studied earlier in the context of nerve transection and brain trauma (Jones et al, 2000).…”

“…Our interpretation, based on the failure of systemic LPS to increase this transcript, is that a rise in GC levels does not by itself explain the intensified presence of the message. However, it is possible that inflammatory signals interact in complex ways to the stress-induced GC effect; once infused in the brain, LPS is able to induce Cd83 in microglia only in the absence of GC receptor signaling (Glezer et al, 2007). Thus, more investigation is required for understanding the signaling implicated in Cd83 transcription in the presence of stressors.…”

Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury

“…Recent reports have suggested that Lcn2 may play a similar role in sensitizing microglia and astrocytes in vitro to cell death induced by cytotoxic agents such as nitric oxide (Lee et al, 2007(Lee et al, , 2009). In the CNS, expression of Lcn2 has been reported in the choroid plexus in response to peripheral lipopolysaccharide (LPS) administration (Marques et al, 2008), as well as in the striatum after intrastriatal injections of LPS (Glezer et al, 2007). Its expression was also reported to be upregulated in a microarray analysis of SCI tissue (De Biase et al, 2005).…”