Over the past several decades, lipid products have been found to exert both proinflammatory effects (e.g., prostaglandins and leukotrienes) and antiinflammatory activities (e.g., lipoxins and products derived from docosahexaenoic acid, including resolvins, protections, and moresins). Now, Chiang et al. describe a previously unrecognized role of GPR18 as a receptor for resolvin (Rv) D2 that stimulates efferocytosis and mediates the resolution of inflammation.

GPR18, which is expressed on the surface of polymorphonuclear neutrophils (PMNs), monocytes, and macrophages, was identified as a receptor for RvD2 using unbiased GPCR–β-arrestin–based screening and functional sensing systems. Receptor–ligand interaction enhanced the innate immune functions (chemotaxis, transmigration, and phagocytosis) of these leukocytes and accelerated the resolution of various types of acute inflammation (caused either by infectious agents or after sterile ischemia-reperfusion injury). The infusion of RvD2 in infected mice impressively reduced the intensity of acute inflammatory responses (which often lead to tissue injury) and enhanced bacterial clearance. Experiments in GRP18-deficient mice confirmed the role of RvD2 in the resolution of inflammation.

Acute inflammatory responses, unless carefully regulated, can lead to substantial tissue damage that may become irreversible, resulting in fibrosis and loss of tissue or organ function. In some cases, for example in acute streptococcal pneumonia, an intense acute inflammatory response with a large buildup of PMNs, extensive edema, fibrin deposition, and hemorrhage resolves within 2–3 days, leaving behind normal lung tissue. The paper by Chiang et al. suggests that high levels of resolvins in the lung parenchyma have an important role to play, and the outcome of other infectious pneumonias may also depend on the appearance, or lack thereof, of resolvins and related lipids. However, unless tightly regulated, excessive activation of the innate immune responses stimulated by the RvD2–GRP18 axis could lead to tissue-damaging inflammatory responses. Perhaps there is a built-in mechanism (such as loss of cell surface receptors like GPR18) that automatically shuts these responses down? Further work will be required to determine whether it will be possible to target the resolvin system as a therapeutic intervention in human inflammatory disorders.

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J. Exp. Med.