Netrins & Semaphorins: Novel regulators of the immune response.

Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions.

Netrins as prophylactic targets in skeletal diseases: A double-edged sword?

The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For example, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate-immune functions of the netrin family of proteins, and summarize their therapeutic potential.