Saturday, 12 April 2014

The Ying and Yang of Science relating to macrophages

Ridderstad Wollberg A, Ericsson-Dahlstrand A, Juréus A, Ekerot P, Simon S, Nilsson M, Wiklund SJ, Berg AL, Ferm M, Sunnemark D, Johansson R. Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. Proc Natl Acad Sci U S A. 2014. [Epub ahead of print]

One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leucocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leucocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed. Here, we demonstrate CX3CR1 mRNA expression on inflammatory cells within active plaque areas in MS brain autopsies. To test whether blocking CNS infiltration of peripheral leucocytes expressing CX3CR1 would be a suitable treatment strategy for MS, we developed a selective, high-affinity inhibitor of CX3CR1 (AZD8797). The compound is active outside the CNS and AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE resulted in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. This treatment strategy is mechanistically similar to, but more restricted than, current very late antigen-4-directed approaches that have significant side effects. We suggest that blocking CX3CR1 on leucocytes outside the CNS could be an alternative approach to treat MS.


CXCR1 is the interleukin 8 receptor that helps cells migrate in relation ot chemokine (cell products that act as a directional actracttant to cells). In this case

Blockade of a chemokine CXCR1 = GOOD

Bellavance MA, Gosselin D, Yong VW, Stys PK, Rivest S. Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity. Brain Struct Funct. 2014  [Epub ahead of print]

Excitotoxicity underlies neuronal death in many neuropathological disorders, such as Alzheimer's disease and multiple sclerosis. In mouse models of these diseases, disruption of CX3CR1 signaling has thus far generated data either in favour (above) or against a neuroprotective role of this crucial regulator of microglia and monocyte functions. In this study, we investigated the recruitment of circulating PU.1-expressing cells following sterile excitotoxicity and delineated the CX3CR1-dependent neuroprotective functions of circulating monocytes versus that of microglia in this context. WT, CX3CR1-deficient and chimeric mice were subjected to a sterile excitotoxic insult via an intrastriatal injection of kainic acid (KA to stimulate glutamate (a nerve transmitter) receptors), a conformational analog of glutamate. Following KA administration, circulating monocytes physiologically engrafted the brain and selectively accumulated in the vicinity of excitotoxic lesions where they gave rise to activated macrophages. Monocyte (from blood)-derived macrophages completely vanished upon recovery and did thus not permanently seed the brain. Furthermore, 
CX3CR1 deletion significantly exacerbated neuronal death, behavioral deficits and activation of microglia cells following sterile excitotoxicity. CX3CR1 disruption also markedly altered the blood levels of patrolling monocytes 24 h after KA administration. The specific elimination of patrolling monocytes of mice conditioned with chemotherapy provided direct evidence that these circulating monocytes are essential for neuroprotection. Taken together, these data support a beneficial role of CX3CR1 signaling during excitotoxicity.

Excitoxicityy which is were nerve cells stimulate themselves too much and die occurs in stroke and make be a problem in MS also in this case

Blockade of a chemokine CXCR1 = BAD

Therefore what should be done, not try the inhibitor, or try it with the risk it makes things worse. Macrophages are part of the damaging machinery but they are also part of the repair machinery. What is the balance?

3 comments:

  1. It's Yin and Yang! And you guys know what you're doing, right? PhDs and everything? Thank God Dr Dre is around to beef up the grammar credentials of this blog.

    ReplyDelete
    Replies
    1. I was never any good at Ingrish problem with dyslexia and my 5cm smartphone doesnt have spell check.
      :-)

      Delete
    2. Now I feel bad for what I said

      Delete

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