UCSF UC San Francisco Previously Published Works Title The multifaceted functions of neutrophils. Permalink https://escholarship.org/uc/item/9p7275kj Journal Annual review of pathology, 9(1) ISSN 1553-4006 Authors Mayadas, Tanya N Cullere, Xavier Lowell, Clifford A Publication Date 2014 DOI 10.1146/annurev-pathol-020712-164023 Peer reviewed eScholarship.org Powered by the California Digital Library University of California PM09CH09-Mayadas ARI 13 December 2013 14:45 The Multifaceted Functions of Neutrophils Tanya N. Mayadas,1 Xavier Cullere,1 and Clifford A. Lowell2 1Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 20115; email: [email protected] 2Department of Laboratory Medicine, University of California, San Francisco, California 94143; email: [email protected] Annu. Rev. Pathol. Mech. Dis. 2014. 9:181–218 Keywords First published online as a Review in Advance on recruitment, receptors, cytotoxic functions, adaptive immunity, September 16, 2013 disorders, chronic diseases The Annual Review of Pathology: Mechanisms of Disease is online at pathol.annualreviews.org Abstract This article’s doi: Neutrophils and neutrophil-like cells are the major pathogen-fighting 10.1146/annurev-pathol-020712-164023 immune cells in organisms ranging from slime molds to mammals. Cen- Copyright c 2014 by Annual Reviews. tral to their function is their ability to be recruited to sites of infection, All rights reserved to recognize and phagocytose microbes, and then to kill pathogens Annu. Rev. Pathol. Mech. Dis. 2014.9:181-218. Downloaded from www.annualreviews.org through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial pep- Access provided by University of California - San Francisco UCSF on 08/18/15. For personal use only. tides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primor- dial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital dis- orders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells estab- lish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases. 181 PM09CH09-Mayadas ARI 13 December 2013 14:45 INTRODUCTION In this article, we aim both to revisit well-established principles of neutrophil func- Multicellular organisms face a constant chal- tion during inflammation and host defense— lenge of surviving in an environment containing including their production, recruitment, and unicellular pathogens. Phagocytes have evolved killing capacities—and to illuminate many of as specialized cells that engulf and kill invad- the newer findings on the contribution of these ing pathogens to protect the host against mi- cells to other aspects of immunity. The purpose croorganisms. They are the major cellular arm of this exercise is to renew and stimulate dis- of the innate immune system, which is common cussion on how processes fundamental to neu- to species throughout the evolutionary tree. In- trophil function may uniquely influence disease deed, the survival of primitive organisms—for progression. We focus on those studies that re- example, insects, which lack adaptive immune veal the growing appreciation of the complex- cells such as lymphocytes—relies on the func- ity of neutrophil function both in normal im- tion of their innate immune phagocytes (1). In mune responses and during immune-mediated humans, neutrophils account for 50% to 70% disease states. of all circulating leukocytes, and they are the first line of host defense against a wide range of infectious pathogens including bacteria, fungi, and protozoa. Neutrophils are generated at a NEUTROPHIL HOMEOSTASIS rate of 1011 per day, which can increase to 1012 Neutrophils are formed within the bone per day during bacterial infection. Thus, not marrow during hematopoiesis in response surprisingly, 55% to 60% of the bone mar- to several cytokines, principally granulocyte row is dedicated to their production (2). Neu- colony–stimulating factor (G-CSF) (12). The trophils are terminally differentiated and rela- major determinants of the total number of neu- tively short lived. Traditional estimates based trophils in the body are their rate of production, on ex vivo survival in culture or on half-life af- their storage in and egress from the bone mar- ter adoptive transfer suggested that these cells row, and their survival in and clearance from the survive for only 8–12 h in the circulation and up blood. Entry into the tissues during inflamma- to 1–2 days in tissues, with their turnover de- tory responses can also affect overall neutrophil layed or accelerated during the inflammatory numbers. The ability of an organism to main- response (3–5). More modern approaches us- tain a balance between neutrophil production ing deuterium labeling methods in vivo sug- and turnover, while adapting to environmental gest that under homeostatic conditions, human challenge, implies that there must be a molec- neutrophils may have a circulatory life span up ular process for measuring neutrophil numbers to 5 days (6). Although this dramatically dif- at any given time. The existence of some form ferent view of neutrophil half-life is somewhat of a “neutrostat” that measures neutrophil controversial (7, 8), these types of more up- numbers and adjusts them accordingly remains Annu. Rev. Pathol. Mech. Dis. 2014.9:181-218. Downloaded from www.annualreviews.org dated immunological investigations are chang- very controversial (13). However, recently described feedback loops certainly contribute Access provided by University of California - San Francisco UCSF on 08/18/15. For personal use only. ing our overall perception of neutrophil func- tion in immunity. Whereas researchers once to neutrophil homeostasis under resting and believed that neutrophils were present only inflammatory disease conditions. during the acute phase of the inflammatory re- One such feedback loop was discovered in sponse, functioning only as pathogen killers, studies of adhesion molecule [CD18, E/P/L- we now appreciate that neutrophils can shape selectin, or CD11a (LFA-1)]–deficient mice. the immune landscape by communicating with In these animals, neutrophil egress from the macrophages, dendritic cells (DCs), and cells of peripheral blood is reduced; hence, the animals the adaptive immune response through direct display significant neutrophilia. Under steady- cell-cell contact or soluble mediators (9–11). state conditions, senescent neutrophils are 182 Mayadas · Cullere · Lowell PM09CH09-Mayadas ARI 13 December 2013 14:45 engulfed by tissue macrophages [primarily in sense low neutrophil numbers remains unclear. the liver, spleen and bone marrow (14)], which However, very recent results suggest that this then initiate anti-inflammatory signals via ex- sensing pathway depends on the innate immune Granulocyte pression of PPARγ (peroxisome proliferator– receptor Toll-like receptor (TLR) 4 and its macrophage activated receptor γ) and LXR (liver X recep- signaling adapter Toll/interleukin-1 receptor colony–stimulating tor) (15). These anti-inflammatory signals, in (TIR) domain–containing adapter-inducing factor (GM-CSF): turn, lower the steady-state production of inter- interferon-β (TRIF), because antibody- a classical cytokine leukin (IL)-23 by macrophages. IL-23 is a well- mediated depletion of neutrophils fails to cause that promotes granulopoiesis and established inflammatory cytokine that induces G-CSF elevation or progenitor proliferation primes neutrophils for IL-17 production by T lymphocytes, natural in mice lacking TLR4 or TRIF (20). enhanced cytotoxic killer (NK) cells, and natural killer T (NKT) Most studies have focused on G-CSF and responses cells, which, in turn, induces production of GM-CSF as the ultimate cytokines that reg- Toll-like receptors G-CSF and granulocyte macrophage colony– ulate neutrophil production, but this is clearly (TLRs): a family of stimulating factor (GM-CSF) by stromal cells, too simple a view, given that mice lacking one or intracellular and driving granulopoiesis and inflammation (16). both of these cytokines still have approximately extracellular PRRs that engage the Adhesion molecule–deficient mice have high 20% of the normal level of mature neutrophils intracellular steady-state levels of IL-23 and IL-17, due in their blood (22). Indeed, these cytokine- transcriptional to reduced egress of neutrophils out of the deficient animals can also mount increased machinery to promote blood and hence reduced neutrophil uptake by neutrophil production in response to inflam- synthesis and secretion macrophages, leading to elevated G-CSF (17). matory stimuli, a process termed emergency of pro-inflammatory cytokines Genetic depletion of IL-23 in CD18 knockout granulopoiesis (23). That hematopoietic pro- mice reverses their neutrophilia, supporting the genitors can ramp up production of granulo- model that the rate of phagocytosis of apoptotic cytes in response to inflammatory or pathogen neutrophils regulates their production via an challenge, even in the absence of canonical IL-23–IL-17 axis (18). Similarly, mice lacking granulopoiesis-stimulating cytokines, indicates the