Cytokines and Chemokines in Stroke

Introduction

Cells involved in the immune system need to be tightly interconnected to elaborate a collaborative and well-organized response against noxious stimuli. With this aim, cells communicate either by direct contact mediated by different plasma membrane molecules or by the synthesis and release of small proteins called cytokines . These cytokines are produced in the earliest stages of cellular activation, alerting other cells of the existence of an on-going immune response. In addition, at later phases, they may participate in resolution and repair of the inflamed tissue. In some instances they exert a local effect, whereas in others they may also act on distant targets. Their functions include the regulation of innate immunity and inflammation including the recruitment of leukocytes to the conflictive region (mediated by specific cytokines known as chemokines ), the control of adaptive immunity, and the generation of newborn cells derived from hematopoietic precursors, among others. In the context of stroke, we will focus on the role of cytokines and chemokines on innate immune response and inflammation including the mechanisms for its resolution, and on some of the active reparative processes that take place in the injured brain.

Cytokines as Signaling Molecules in the Innate Immune Response of the Ischemic Brain

Innate immunity is an evolutionary old defense system that generates a fast inflammatory response that is generic to all types of pathogens or tissue damages and does not confer immune memory to the host.

The innate immune system is activated after stroke as a consequence of hypoxia-mediated cell death, which leads to the release of tissue “danger signals” known as damage-associated molecular patterns (DAMPs), like fibrinogen, heat shock proteins, or extracellular ATP. Recognition of DAMPs by pattern recognition receptors, such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs), activates downstream signaling pathways in immune cells, including nuclear factor-κB, mitogen-activated protein kinases (MAPK), and type-I interferon pathways. This culminates in the upregulation of proinflammatory mediators, including cytokines and chemokines that, in turn, activate resident glial cells, mainly microglia, and recruit blood-borne cells to the ischemic tissue . Accumulating evidence shows that postischemic inflammation plays critical roles in stroke outcome and that innate immunity can be associated with not only damage to the host tissue but also resolution of inflammation and neurorepair.