Roles of neutrophil granule proteins in orchestrating inflammation and immunity

Abstract

Neutrophil granulocytes form the first line of host defense against invading pathogens and tissue injury. They are rapidly recruited from the blood to the affected sites, where they deploy an impressive arsenal of effectors to eliminate invading microbes and damaged cells. This capacity is endowed in part by readily mobilizable proteins acquired during granulopoiesis and stored in multiple types of cytosolic granules with each granule type containing a unique cargo. Once released, granule proteins contribute to killing bacteria within the phagosome or the extracellular milieu, but are also capable of inflicting collateral tissue damage. Neutrophil-driven inflammation underlies many common diseases. Research over the last decade has documented neutrophil heterogeneity and functional versatility far beyond their antimicrobial function. Emerging evidence indicates that neutrophils utilize granule proteins to interact with innate and adaptive immune cells and orchestrate the inflammatory response. Granule proteins have been identified as important modulators of neutrophil trafficking, reverse transendothelial migration, phagocytosis, neutrophil life span, neutrophil extracellular trap formation, efferocytosis, cytokine activity, and autoimmunity. Hence, defining their roles within the inflammatory locus is critical for minimizing damage to the neighboring tissue and return to homeostasis. Here, we provide an overview of recent advances in the regulation of degranulation, granule protein functions, and signaling in modulating neutrophil-mediated immunity. We also discuss how targeting granule proteins and/or signaling could be harnessed for therapeutic benefits.

Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test

“… 5 Moreover, MPO may increase Mac-1 expression, cause further MPO release from neutrophils, and delay their intrinsic apoptosis. 46 , 47 This MPO-dependent feed-forward loop amplifies the response of neutrophils, thereby prolonging inflammation, causing local tissue damage, and leading to chronic inflammatory conditions. 46 As such, the reduction of the MPO level is regarded as another crucial condition to alleviate the second phase of carrageenan-induced inflammatory response.…”

“… 46 , 47 This MPO-dependent feed-forward loop amplifies the response of neutrophils, thereby prolonging inflammation, causing local tissue damage, and leading to chronic inflammatory conditions. 46 As such, the reduction of the MPO level is regarded as another crucial condition to alleviate the second phase of carrageenan-induced inflammatory response. 48 In the present study, we indicated that compared to the carrageenan-injected rats, pretreatment with compound 13b at all doses tested counteracted the increased MPO level in paw tissue, and this effect was similar to that provided by indomethacin.…”

Neutrophil NETworking in ENL: Potential as a Putative Biomarker: Future Insights

“…The release of granular protein is a tightly regulated receptor-coupled process, mediated by distinct signaling events for each granule type, allowing the selective, differential, hierarchical mobilization of distinct subsets with the tertiary granules being the most readily mobilizable upon activation followed by specific granules, the primary ones bringing up the rear. This distinct readiness of different granule subsets toward degranulation modulates neutrophil heterogeneity and functional versatility by altering the neutrophil cell-surface protein composition that generates different cellular phenotypes underlying remarkable neutrophil plasticity ( 28 , 53 , 63 – 65 ).…”

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

“…The multifaceted characteristics of neutrophils are not surprising considering their nature to be already pre-equipped with a whole battery of substances stored in their many granules [ 2 , 5 , 8 , 149 ] and the surface expression of a multitude of chemokine and cytokine receptors [ 9 ], pattern recognition receptors [ 150 ], C-type lectin receptors [ 150 ], Fc receptors [ 150 ], carcinoembryonic antigen-related cell adhesion molecule (CEACAM)3 [ 151 ], sialic acid-binding immunoglobulin-like lectin (Siglec)-14 [ 152 ], leukocyte immunoglobulin-like receptors [ 153 ] and complement receptors of the β-integrin family [ 154 ] that enable a rapid response to almost any encountered stimuli.…”

“…The sequential release occurs in the opposite direction of their formation, meaning that the secretory vesicles are the first to be released, then the tertiary granules, the secondary granules and, at last, the primary granules [ 3 ]. The differential release of the various granules of the neutrophils may contribute to the neutrophil heterogeneity, versatility and plasticity observed under various pathophysiological conditions [ 7 , 8 ]. This may also explain why the premature neutrophils released to the circulation exhibit different properties than the mature neutrophils, and why the neutrophils, during their short lifespan, exhibit different traits depending on the stimuli perceived and their stage of differentiation.…”