Complex gene-dependent and-independent mechanisms control daily rhythms of hematopoietic cells

The abundance and behaviour of all hematopoietic components display daily oscillations, supporting the involvement of circadian clock mechanisms. The daily variations of immune cell functions, such as trafficking between blood and tissues, differentiation, proliferation, and effector capabilities are regulated by complex intrinsic (cell-based) and extrinsic (neuro-hormonal, organism-based) mechanisms. While the role of the transcriptional/translational molecular machinery, driven by a set of well-conserved genes (Clock genes), in nucleated immune cells is increasingly recognized and understood, the presence of non-transcriptional mechanisms remains almost entirely unexplored. Studies on anucleate hematopoietic components, such as red blood cells and platelets, have shown that auto-sustained redox reaction cycles persist and operate in mammals. This opens to the possibility that transcriptional and non-transcriptional circadian mechanisms might coexist in nucleated immune cell populations, potentially complementing each other. It is becoming increasingly clear that disruption of the circadian rhythm at the central level (core clock) is strongly implicated in a plethora of diseases that are associated with maladaptive immune responses. On the other hand, several evidence imply that dysregulated immune activity (e.g. excessive inflammation) may alter/disrupt the proper functioning of peripheral clocks. This knowledge paves the way to the exploitation of chronobiological concepts in clinical practice. A better comprehension of various transcriptional/translational and biochemical mechanisms that maintain rhythmicity in immune system activities, as well as the many factors (host-derived, microbiota-derived, environment) that can alter or disrupt these processes, will facilitate the development of novel chrono-immunotherapeutic approaches.