Year: 2015
Type: editorial
Abstract: Macrophages play a dual role in angiogenesis. On the one hand, they can assist with revascularization of hypoxic areas, such as ischaemic muscle. On the other hand, they can promote inflammation and tumorigenesis. The Jekyll–Hyde nature of macrophages is incompletely understood and needs further elucidation to treat diverse disorders that involve macrophages including muscle ischaemia (including coronary artery disease), tumorigenesis (role of M2 macrophages), HIV persistence (may also involve M2 macrophages) and autoimmunity (Herbein & Varin 2010) (Liu et al. 2012) (Stahl et al. 2013). Shb is an adaptor molecule that is involved in signalling downstream of several receptors, including VEGF. Deficiency of Shb leads to both vascular and immune defects, with Th2 polarization of T lymphocytes and vascular defects (Gustafsson et al. 2011). Given that circulating immune cells are involved in revascularization, Nikpour et al. teased apart the relative contribution of myeloid cells versus endothelial cells in modulating the vascular defects (Nikpour et al. 2015). Intraperitoneal injection of VEGF, followed by lavage, revealed no difference in neutrophil influx in either wild-type or Shb-deficient mice. However, the population of CXCR4-positive monocytes/macrophages were reduced in Shb-deficient mice compared with wild-type mice. This defect appeared specific to VEGF, because when another inflammatory stimulus, tumour necrosis factor alpha, was used, no difference was observed in CXCR4-positive monocytes/macrophages. Finally, in an elegant set of bone marrow experiments, the investigators demonstrated that the poor recovery to hindlimb ischaemia is an intrinsic vascular defect rather than due to functional status of the myeloid lineage. What lessons can be learned here? It appears that this study has identified two classes of macrophages, one of which is CXCR4 positive, and requires VEGF for optimal recruitment. On the other hand, Shb deficiency does not affect response to tumour necrosis factor alpha. A major question is what are the role of CXCR4-positive macrophages, as they seem to require Shb for an optimal response to VEGF, but not TNFa? Of interest, CXCR4 is a coreceptor for human immunodeficiency virus, so loss of Shb might affect susceptibility to HIV (Nikpour et al. 2015). CXCR4 has been shown to be important in T cell tropic HIV infection, while CKR-5, also called CC-CKR5 or CCR-5, is thought to be more important in macrophage tropic HIV infection. Of interest, CD34-positive progenitor cells, which can give rise to macrophages as well as endothelial cells, express CXCR4 and can be infected by HIV (Deichmann et al. 1997). Shb may represent a lineage marker in CD34-positive progenitor cells, that when lost, results in a skewing towards VEGFR1+ macrophages (Fig. 1). Finally, is there a therapeutic role in targeting Shb as an anti-inflammatory therapeutic? The author has no conflicts of interests.
Source: Acta Physiologica
DOI: 10.1111/apha.12504
Author: J. L. Arbiser
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,150
OpenAlex ID: W2067314157