Circadian immune circuits

Abstract

Immune responses are gated to protect the host against specific antigens and microbes, a task that is achieved through antigen- and pattern-specific receptors. Less appreciated is that in order to optimize responses and to avoid collateral damage to the host, immune responses must be additionally gated in intensity and time. An evolutionary solution to this challenge is provided by the circadian clock, an ancient time-keeping mechanism that anticipates environmental changes and represents a fundamental property of immunity. Immune responses, however, are not exclusive to immune cells and demand the coordinated action of nonhematopoietic cells interspersed within the architecture of tissues. Here, we review the circadian features of innate immunity as they encompass effector immune cells as well as structural cells that orchestrate their responses in space and time. We finally propose models in which the central clock, structural elements, and immune cells establish multidirectional circadian circuits that may shape the efficacy and strength of immune responses and other physiological processes.

Figure 1.

Circadian immune circuits. Circadian regulation of innate immunity requires the coordinated action of at least three compartments: neurons of the SCN (and downstream endocrine organs), structural cells in peripheral tissues, and immune cells. The SCN integrates photic cues, which represent the main entrainment signals; however, the immune system can be also resynchronized by feeding or during infections. In this model, circadian information “flows” through these compartments, forming what we refer to as circadian immune circuits. We organize the distinct compartments of these circuits as those associated with the central clock or other entrainment cues (A), which deliver signals to structural (B) and/or innate immune cells (C) in peripheral organs. The circuits are organized such that structural and innate immune cells reciprocally communicate to orchestrate immune responses or specific physiological events (D). The upper diagram shows a nonexhaustive list of circadian immune circuits identified from the literature, of which some are highlighted by color lines and are referred to in the text and detailed in the lower table. All circuits shown here are detailed in Table 1. Eos., eosinophils; Baso., basophils; TRM, tissue-resident macrophages.

Figure 2.

Modeling the architecture of circadian immune circuits. (A) Depiction of the classical model of circadian immune circuits whereby circadian clocks in innate immune subsets are under direct control of the master clock. (B) The model is refined by recent observations that consider at least three elements in the circuit (SCN and structural and immune cells). The presence or depletion of the internal clock in each component of the circuit leads to specific circadian patterns in immune response or tissue physiology. Rescue of a functional clock in specific components in an otherwise arrhythmic mouse (models 4 and 5) will be needed to understand how the circuits are actually organized. (C) Integrating current and future analyses proposed in the text and shown in B will enable building a more accurate model of how these circuits work, including defining whether peripheral clocks sense diurnal changes and deliver circadian cues to the other components of the circuit.