Alarmins link neutrophils and dendritic cells

Abstract

Neutrophils are the first major population of leukocyte to infiltrate infected or injured tissues and are crucial for initiating host innate defense and adaptive immunity. Although the contribution of neutrophils to innate immune defense is mediated predominantly by phagocytosis and killing of microorganisms, neutrophils also participate in the induction of adaptive immune responses. At sites of infection and/or injury, neutrophils release numerous mediators upon degranulation or death, among these are alarmins which have a characteristic dual capacity to mobilize and activate antigen-presenting cells. We describe here how alarmins released by neutrophil degranulation and/or death can link neutrophils to dendritic cells by promoting their recruitment and activation, resulting in the augmentation of innate and adaptive immune responses.

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…[5][6][7][8][9] To ensure their efficient removal, physiologically dying cells emit 'find-me signals' (e.g., fractalkine (CX3CL1)) to recruit antiinflammatory phagocytes, 10 or release 'keep-out' signals (e.g., lactoferrin), to avoid inflammatory cells. 7,11,12 Along with these soluble signals, clearance of dying cells is regulated by a constellation of 'eat me' signals, a collective term for surfacetethered proteins, phospholipids or protein complexes facilitating cellular engulfment by binding to phagocytic receptors on immune cells (Figure 1). 5,7,11,12 Viable cells avoid phagocytic clearance through retained presentation of surface-associated 'don't eat me' signals.…”

“…7,11,12 Along with these soluble signals, clearance of dying cells is regulated by a constellation of 'eat me' signals, a collective term for surfacetethered proteins, phospholipids or protein complexes facilitating cellular engulfment by binding to phagocytic receptors on immune cells (Figure 1). 5,7,11,12 Viable cells avoid phagocytic clearance through retained presentation of surface-associated 'don't eat me' signals. 6,13 On the other hand, recognition and clearance of dying cells is affected by the molecular nature, spatiotemporal frame and overall balance of pro-phagocytic and antiphagocytic determinants, 14 for example, dying cells tend to reduce 'don't eat me' signals while increasing the 'eat Box 1 Major cell death pathways and their immunobiological profiles Apoptosis:…”

“…47 me' signals on the surface. 5,7,11,12 Excessive cell death events can overwhelm the clearance capacity of phagocytes thereby causing a persistence of late apoptotic or secondary necrotic cells capable of disturbing tissue homeostasis.…”

“…Antitumour immunity resulting from these treatment scenarios is expected to culminate into cancer cell-eliminating activity exerted by CTLs through IFN-γ (exerts cytostatic effects and polarizes immune cells towards type I-immune reactions), FasL-CD95 interactions (exerts extrinsic apoptosis) or granzymeperforins secretion (exerts direct cytotoxicity through perforin-driven membrane-pore formation followed by granzyme-induced cell death) High-hydrostatic pressure In topotecan-treated ovarian cancer patients, overall CALR levels either do not or even negatively correlate with levels of phagocytosis-associated genes 49,52 Phagocytic clearance, cancer cell death and immunotherapy AD Garg et al cytokines and causes an exaggerated polarization of MФ into a pro-tumorigenic phenotype (owing to the production of protumorigenic cytokines TGF-β and IL-10) 88 , while promoting the production of anti-inflammatory factors. 5,7,11,12,88 Instead, APCs that carry out immunogenic phagocytosis present TAAs to CD4 + T cells in the presence of heightened levels of co-stimulatory molecules and increased levels of proinflammatory cytokines (e.g., IL-6/IL-12/IL-1β) (Figure 1). 25,52,55 This, in concert, facilitates the differentiation of Th1 cells that orchestrate a type-I immunity-based anticancer programme (consisting of IFN-γ-driven cancer-directed cytostatic effects and suppression of Treg differentiation).…”

IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation

“…In turn, necrotizing cells lose their membrane integrity, resulting in the release of intracellular components that stimulate the immune response through damage-associated molecular pattern receptors (7). Over the past decade, a number of endogenous molecules, now known as alarmins, have been identified by their ability to induce leukocyte recruitment and activation and also to cause maturation of APCs (8). Most alarmins are constitutively expressed under homeostatic conditions and released upon necrosis (9)(10)(11)(12)(13)(14), but not apoptosis (13,15,16).…”