This Week in The Journal

Neutrophils Compensate for Macrophage Loss in Injured PNS

Jane A. Lindborg, Matthias Mack, and Richard E. Zigmond

After a peripheral axon is cut, the distal portion must be removed before the proximal stump can regrow. This process begins with active disintegration of the distal segment, followed by local breakdown of the blood-nerve barrier and dedifferentiation of myelinating Schwann cells. Schwann cells then begin to phagocytose myelin and secrete cytokines to attract additional phagocytes from the blood. The first blood-borne cells to arrive are neutrophils, which remove some debris near the injury site before undergoing apoptosis. But the main scavengers of cellular debris are macrophages. These cells also secrete trophic factors that attract remyelinating Schwann cells and promote axon growth (Gaudet et al 2011 J Neuroinflammation 8:110).

Degenerating fibers (outlined by solid lines) and phagocytic cells containing degenerating myelin and lipid vacuoles (dotted lines) are present in similar amounts in wild-type (left) and CCR2-deficient nerves (right). See Lindborg et al. for details.

Despite the apparent importance of macrophages in debris clearance from damaged peripheral nerves, knocking out the receptor CCR2, which allows blood-borne macrophages to respond to chemoattractants, does not impair myelin removal (Niemi et al. 2013 33:16236). In fact, Lindborg et al. found that more myelin had been removed within 3 days of sciatic nerve transection in CCR2-deficient mice than in controls. Although this accelerated clearance was likely helped by a slight increase in the number of phagocytic Schwann cells in mutant nerves, the bulk of the clearance was mediated by neutrophils, which were present along the entire length of the distal stump and entered the nerve in larger numbers in CCR2-deficient mice than in controls. The larger influx of neutrophils was attributable primarily to a sustained increase in the levels of neutrophil chemoattractants in injured nerves of mutant mice. Importantly, depleting neutrophils from the blood reduced myelin clearance in both wild-type and CCR2-deficient mice, with a larger effect in the mutants.

These data are consistent with previous reports indicating that neutrophils contribute to myelin clearance in wild-type mice. Moreover, they show that neutrophils can compensate for loss of macrophages. It should be noted, however, that macrophages that reside in the nerve are also likely to contribute to debris clearance when blood-borne macrophages are not recruited. Indeed, because neutrophils promote phagocytosis by macrophages, it is possible that the increased infiltration of neutrophils in CCR2-deficient mice leads to increased phagocytosis by resident macrophages. Future work should investigate this possibility.

Variation in SNAP-25 Promoter Increases Schizophrenia Risk

Josselin Houenou, Jennifer Boisgontier, Annabelle Henrion, Marc-Antoine d'Albis, Anne Dumaine, et al.

(see pages 10389–10397)

Schizophrenia is a multifaceted psychiatric condition whose symptoms include hallucinations, delusions, dampened emotions, poor executive control, and attention deficits. Its biological basis remains poorly understood, but it is thought to result from abnormal development of neural circuits, particularly those involving dopaminergic and glutamatergic signaling. This abnormal development stems from environmental factors impinging on numerous genetic risk factors, most of which exert small effects on their own. In fact, variations at more than 100 genetic loci have been linked to schizophrenia risk. Because most of these variations occur outside protein-coding regions, they are thought to act by altering expression of nearby genes, particularly genes involved in neuronal excitability or synaptic transmission. Interestingly, many of these variations have also been linked to bipolar disorder.

A polymorphism at rs6039769 in the promoter region of the gene encoding SNAP25, a protein involved in synaptic vesicle release, was previously linked to a form of bipolar disorder that often includes psychotic symptoms (Etain et al. 2010 Mol Psychiatry 15:748). Possession of the C allele was associated with increased expression of SNAP25 in the prefrontal cortex. Because increased levels of SNAP25 have been found in CSF of schizophrenia patients, and because other polymorphisms in SNAP25 have been linked to schizophrenia, Houenou et al. asked whether the rs6039769 C allele also increases schizophrenia risk. Indeed, the variant was found significantly more often in schizophrenia patients than in controls. Although the variation did not affect the overall expression of SNAP25 in postmortem prefrontal cortex of schizophrenia patients or controls, it appeared to alter the relative expression of two SNAP25 variants selectively in patients. In addition, the amygdala was larger and showed greater functional connectivity with the prefrontal cortex in men homozygous for the rs6039769 C allele than in carriers of the A allele.

These results provide more evidence that altered expression of genes involved in synaptic transmission contributes to the pathology of bipolar disorder and schizophrenia. In the case of SNAP25, expression differences might selectively affect interactions between the prefrontal cortex and amygdala. If these results are confirmed in larger studies, future studies involving modest changes in SNAP25 expression in animals might provide further insight into the etiology of these two diseases.